Short answer: probably US 30, most of which had earlier been the Lincoln Highway. Before the Pennsylvania Turnpike opened in 1940, this was the main route from Philadelphia to Pittsburgh, across the mountains of Pennsylvania. My 1951 Rand McNally Road Atlas has a cover that combines regional images with highway shields; the big city skyline representing East Coast is superimposed over a 30 shield. US 30 even had roadside attractions like the ones that became iconic on Route 66: the Ship Hotel, the Coffee Pot, etc.

It’s actually a little ironic to call Route 66 the main western route, as the initial numbering sequence—designating the most major highways with numbers ending in 0 or 1—didn’t include the diagonal from Chicago to St Louis via Oklahoma, Texas, and New Mexico to Southern California. But Route 66, open all year and crossing the Continental Divide via a low pass in New Mexico, quickly became the preferred route west, especially as Southern California’s growth outstripped the San Francisco Bay Area and as cross-country truck traffic grew. By 1950, many states had four-laned portions of the route. Meanwhile, the route via the romantic Desert Southwest made 66 a family vacation favorite and symbol of the “freedom of the open road.”

Paths through Ohio and Pennsylvania weren’t as singular. US 20 better served the steel region of Northern Indiana, Toledo, and Cleveland, then headed east via Erie, Buffalo, Albany to Boston. By 1945, the industrial cities along the Great Lakes were such important destinations for trucks that the Ohio and Indiana turnpikes were routed closer to US 20 than US 30. US 6 crossed northern Pennsylvania via a less-mountainous route, while US 22 was shortest through the central part of the state. US 40, which generally followed the National Road, connects St Louis, Indianapolis, Columbus, Wheeling, and Baltimore. US 30 directly connected Pittsburgh to Philadelphia, but the mountainous terrain made it slow, especially for trucks, and ice and fog often made it hazardous. Using tunnels built 50 years earlier for an aborted railroad, the Pennsylvania Turnpike opened in 1940 to immediate success, cutting in half the time needed to cross Pennsylvania.

East of Philadelphia, the Lincoln Highway—like roads back to colonial days—ran through New Jersey to New York City. Under the numbering scheme, this route became US 1, while US 30 headed southeast to Atlantic City. US 1, of course, was iconic in other ways, connecting Boston to Washington, and running all the way from Maine to Key West.

Though certainly there were professional drivers who knew big parts of the country in their heads, the ways in which the numbered US highway network had been pieced together, determined in part by regional rivalries or funding needs, prior to the Interstate era it was indispensable to have a good road map in the glovebox.

A couple of useful sources: Drake Hokanson’s book The Lincoln Highway: Main Street Across America, and John A. Jakle and Keith Sculle’s book Motoring: The Highway Experience in America.