Hello - I'm glad to meet someone else who has such an avid interest in the Seleucids. While /u/Spaghettix gave an excellent response, I'll just elaborate on some of his points and add a few of my own.

So to begin with, it's important to understand just what the Empire of Seleucus was. It its height, the empire encompassed over 3 million square kilometers of land with a population that was certainly into the tens of millions, that spoke hundreds of languages and could be divided into groups as diverse as Anatolians, Phoenicians, Persians, Jews, Nomads, Syrians, Arabs, and even Indians at one point - to just name a few - and it was all ruled by a Macedonian-Greek dynasty. It encompassed the greater bulk of the modern countries of Syria, Iraq, Iran, Lebanon, and Turkey with minor parts of several others, and at its height it stretched from the shores of the Aegean Sea in the West to the foothills of Afghanistan in the East.

I say these things not because I think the OP has never seen a map depicting the Empire, but simply to give a sheer sense of the scale of what was truly a behemoth. To have even governed it at all, with its immense diversity and constituent peoples (such as the Persians) well accustomed to their own glories was a feat in and of itself. All of this in an era before instantaneous communication - where the the word of the Basileus could only move as fast as a horseman or a boat could carry it.

In this sense it was the Austria-Hungary of its day, except without the benefit of two thousand years of development in governance, communications, and more. A sprawling, multi-cultural empire held together more by the claims and desires of its ruling family than any sort of natural geographical, political, or cultural affiliation between its disparate groups.

Added to the inherent instability of the empire was its tendency for dynastic struggles, no doubt only exacerbated by the fact that such long distances made it easy for relatives to plot against the King, but individual governors were just as inclined to consider themselves too remote and too unassailable by the King in Antioch. These sorts of intrigues were present from the very beginning.

Seleucus I, founder the dynasty was murdered by Ptolemy Ceraunus on the eve of completing his victory over the other Diadochi and claiming the prize of Macedonia for his empire. Antiochus I, his son, was poisoned by a jealous wife while two grandsons of Seleucus - Seleucus Callinicus and Antiochus Hierax - fought a civil war with one another before the former emerged victorious and the latter was supposedly killed by mere robbers while in exile in Egypt. Seleucus Callinicus' son, Seleucus Ceraunus, now the fourth monarcy in the dynasty, was murdered by his own soldiers while on campaign. His successor, Antiochus III was the last Seleucid ruler of any true note, and the only one capable enough to earn the title 'The Great'. 'The Great' Antiochus overreached when he challenged Rome for dominion over Greece, and died at the hands of his own subjects - an impoverished sovereign reduced to looting his own temples to pay his war debts.

Can you detect a pattern yet? Dynastic instability, coupled with strategic vulnerabilities inherent in the empire were far and away the largest contributors to the Empire's fall, which itself was rarely able to enjoy a period of consolidation, or recovery after a setback.

Of the Empire's primary enemies - the Parthians, the Ptolemies, and the Romans - I would only ascribe the Parthians and later the Romans as having a decisive effect on the Empire. The Ptolemies mattered only insofar as the two dynasties constantly warred with one another, and so siphoned off resources that could have better been used to maintain themselves against other threats.

The Parthians were the greatest enemy, devouring the Empire from the East, province by province. The King's attention would always focus most directly on Syria, Southwards towards the Ptolemies, or Westwards towards Anatolia. Meanwhile, from a capitol that lay 4,000 kilometers from his furthest outposts, the Eastern provinces lived in a state of neglectful government, scarcely remembered at times and easily devoured by the rising Parthians who soon swept over the rich heartlands of Persia and down into the fertile valleys of Mesopotamia, forever denying the Seleucid king some of his wealthiest territories and most important recruiting grounds.

When the Romans finally did come, it was merely the last nail in the coffin for any potential Seleucid resurgence.

It's telling to reflect that the son of Antiochus the Great once stood poised on conquering Egypt when a single Roman senator, Gaius Popillius Laenas, could arrive and draw a circle in the sand around the Seleucid King, demanding that before the King stepped outside the circle he would either agree to leave Egypt, or be at war with Rome. The King spared no time in taking his army and leaving.

In the end, I believe the Seleucid Empire died because it was simply too unwieldly, an artificial construct with no real fiber to hold it together. In that sense, it was impossible that it could last for very long and the fact that it managed as well as it did should be viewed as a great accomplishment in and of itself.

Disclaimer: I am not a historian, nor have I read the primary texts that deal with the fall of the Seleucid Empire, however, I have always been interested in the Successor Kingdoms (Diadochi) and will relay what I know.

It is important to understand that Alexander's Empire was overextended and when Alexander died the subsequent infighting and territory grab of his generals was a seriously destabilizing to the region as a whole. Seleucos I was given the satrapy of Babylon, which basically consisted of the land from Mesopotamia to the Indus River, in the second division of Alexander's Empire in 321 BCE and eventually gained control of the Asian part of Antigonos' empire, which consisted of Anatolia and the eastern Mediterranean coast (hereafter referred to as the Levant) after the fall of Antigonos' empire after its final fall at the Battle of Ipsos in 301 BCE. By the time of his assassination in 281 BCE, Seleucos I had recovered the vast majority of Alexander's empire controlling all except for Egypt and Greece. This is all to say that like Alexander's empire the Seleucid Empire was massively overextended from the start.

In relation to your question "Was it internal pressures exploited? Or was it primarily an external threat?" I'd argue that it started with external threats that come along with a hugely overextended empire, but the main factor of the empire weakening was from internal pressures, primarily dynastic struggles and rebellion.

In the reigns of the first monarchs following the death of Seleucos I the capital of the empire was moved from Seleucia (near modern day Baghdad) in the center of the empire to Antioch (modern day Antakya) in the far west of the empire. The moving of the administrative center to the west of the empire alienated its far eastern provinces, and the empire lost about half its territory when the hellenistic Bactrian and the Parthian kingdoms declared themselves independent in 250 BCE. Also, in Anatolia, there were rebellions in Bythinia and Pergamum, and around this same time the first Syrian wars against the Ptolemys began which saw the Seleucids lose the Levant.

Despite being beset on all sides by rival empires and internal rebellion the Seleucid Empire did have a revival period when 18 year-old Antiochos III inherited the throne in 223 BCE. During the reign of Antiochus III the Seleucid Empire restored at least nominal rule over Parthia and Bactria and managed to take back the Levant from the Ptolemies. The empire was largely intact again by 198 BCE.

This was not to last, however as Antiochos III chose to wage war against Rome in spite of advice from Hannibal Barca, yes that Hannibal Barca, who had fled to Syria following the Punic wars. The Seleucids allied themselves with the Aetolian League in Greece against the Romans. However, they were defeated twice at Thermopylae and at Magnesia in 190 BCE. The war effort was not at all helped by giving Hannibal, arguably one of the greatest generals of all time, the rank of admiral rather than giving him a field command. They were forced to make a costly peace with Rome where all their European holdings were ceded to the Romans and all of their holdings in Asia Minor were ceded to Pergamum, which was a close ally of Rome (so close that in 133 BCE, their last king left his kingdom to Rome in his will).

Antiochos III's death in 187 BCE all but marks the end of the Seleucid Empire as a great power. The kingdom fell once more into dynastic struggles, and the eastern provinces were gradually lost due to rebellions and Parthian expansion. The Seleucids tried to extend their influence south, waging a successful war against the Ptolemys, but withdrew despite forcing the main Ptolemaic army back to Alexandria largely because of Rome's threat to intervene in favor of the Ptolemies.

The Seleucids, realizing that conquest was getting to be out of the question, tried to fortify the lands they already controlled both culturally and militarily. They tried to do this through forced Hellenization of its territories which trigger the revolt of the Maccabees which was discussed at length in the subreddit yesterday which cost the Seleucids Judaea. Being preoccupied with the Maccabean revolt other parts of the kingdom began to rebel all but unopposed. This is where the frequent dynastic civil wars really took their toll on the empire. After the death of Antiochos III, nearly every successor to the throne had multiple contenders vying for the position. While there are too many ridiculously complex dynastic struggles to get into here, suffice it to say that the lack of strong leadership at the top further weakened the empire, making it impossible for the Seleucids to defeat the growing power of the Parthians. The Parthians began to take Persian territories almost unchallenged and the Seleucids simply could not defeat them.

By the first century BCE, the Seleucid Empire was an exclusively Syrian empire, controlling only Antioch and a few other Syrian cities. Tigranes, the son-in-law of the famed Mithradates, conquered Syria and put an end to the empire. However, after Mithradates' defeat, the Seleucids restored rule in Syria, but it sadly was not to last. After the Romans finally conquered Pontus, the Seleucids were nothing more than a nuisance, an annoying one at that. Pompey the Great (of the First Truimvirate) finally put an end to all of the madness when he turned Syria into a Roman province in 63 BCE.

So to try and answer your question as directly as I can: I’d argue that the Seleucid Empire died by a thousand cuts, but the cut from Rome caused the empire to bleed out. The empire was largely harassed by the other successor kingdoms the Ptolemys and the Bactrians (arguably a Diadochi), but they did manage to hold off the worst of these threats and in reality ended up taking much more from the Ptolemys than they lost. The Bactrians and the Parthians (but more so the Parthians) constant rebellions took a toll on the empire, but when the empire was united they were able to put these rebellions down. The true end of the empire was the war Antiochos III waged against Rome. While this does play into the Hubris Trope that ancient writers often used, the loss of Anatolia was a massive blow to both the prestige and economy of the empire. Furthermore the threats issued by Rome when the Seleucids were knocking at the door of Alexandria, and the Seleucid capitulation to the Roman demands, demonstrated to their hostile subjects that the empire was weak and sparked rebellion particularly with the Parthians. While a united Seleucid Empire had a chance to put these rebellions down, the leadership was infighting over succession and was not strong enough to win even a single battle against the Parthians from this point forward. The internal dynastic struggles allowed the external threats to tear the empire apart following the defeat by Rome and the empire was never strong enough to reassert the dominance it once had in the region.

Edit - Grammar