While it currently runs east-northeast from Bishop, California, to Provincetown, Massachusetts, the route has been modified several times.

George R. Stewart, author of U.S. 40: Cross Section of the United States of America, initially considered US 6, but realized that "Route 6 runs uncertainly from nowhere to nowhere, scarcely to be followed from one end to the other, except by some devoted eccentric".

The modern US 6 in California is a short, two-lane, north–south surface highway from Bishop to the Nevada state line.

Currently, US 6 begins at US 395 in Bishop and heads north between farms and ranches in Chalfant at the base of the 14,000-foot (4,300 m) western escarpment of the White Mountains.

SR 120 begins here, heading west past Mono Lake through Lee Vining, over Tioga Pass, and through Yosemite National Park to the San Joaquin Valley.

At Warm Springs, SR 375, also known as the "Extraterrestrial Highway", departs to the southeast and US 6 assumes a northeasterly alignment across the Reveille, Pancake, Grant and White Pine ranges.

East of Ely, US 6/US 50 cross the Schell Creek Range, known for verdant forests and meadows and for a large mule deer and elk population.

The highway descends to Spring Valley, then crosses the Snake Range at Sacramento Pass, north of Nevada's second-highest mountain, Wheeler Peak, where a branch road accesses Great Basin National Park.

US 6 enters Utah concurrently with US 50 in a remote portion of the Great Basin Desert; the routes separate at Delta.

After cresting the Wasatch Range via Soldier Summit, the route descends into Utah's coal country, which is where it joins US 191.

US 6 is basically parallel to, or runs concurrently with, I-70 for a significant portion of its length as it generally heads east from the Utah state line thru about half of Denver.

A significant departure from I-70 occurs at Silverthorne where it veers a bit south then north, avoiding the nearly two-mile-long (3.2 km) tunnel on I-70 as it goes under the Continental Divide.

It continues down the Clear Creek valley as it again reaches I-70 at the Loveland Ski Area straddling the eastern mouth of the Eisenhower Tunnel.

The route emerges from the freeway alongside US 85 through Commerce City, where the pair briefly join State Highway 2 (SH 2) before separating at Colorado Boulevard.

At Lincoln, US 6 becomes West "O" Street, Sun Valley Boulevard, and eventually Cornhusker Highway as it moves north of I-80 outside of the city, paralleling I-80 to Gretna.

From the Nebraska state line, US 6 enters Iowa at Council Bluffs, across the Missouri River from Omaha where it intersects I‑29 within the first mile.

It enters the Des Moines metro area along Hickman Road in Waukee and then forms the border between Urbandale to the north and Clive and Windsor Heights to the south.

US 6 directly serves the downtowns of many cities for its length, including Oak Forest, Tinley Park, Moline, Geneseo, Atkinson, Annawan, Princeton, Peru, La Salle, Ottawa, Channahon, and Joliet—unlike US 20, which, in Illinois, mainly consists of freeway sections that bypass the cities US 6 serves.

It travels through Edgerton, then just south of Bryan before it passes through Napoleon, Bowling Green, and Fremont, before turning northeast toward Sandusky Bay and Lake Erie.

Near the east side of the park, US 6 intersects the Palisades Interstate Parkway and runs concurrently with it to the historic Bear Mountain Bridge, where US 6 is joined by US 202 and is narrowed to a rural two-lane road as it crosses the Hudson River with scenic views of the Hudson Highlands.

In western Connecticut, US 6 either closely parallels or is concurrent with I-84, serving as the local route in the suburbs of Danbury, Waterbury, Bristol, and Hartford.

In eastern Connecticut, US 6 is one of the principal routes connecting Hartford and Providence, passing through the small urban areas of Willimantic and Danielson.

The unsigned portion of the Connecticut Turnpike then meets with US 6 shortly before crossing the Rhode Island state line.

US 6 runs approximately 117.5 miles (189.1 km) in Massachusetts, paralleling I-195 between Providence and Wareham, and serves as the local business route.

[4] By the time the final plan was approved in late 1926, a second section had been added, from the New York–Pennsylvania border at Port Jervis, New York, west to US 120 in Kane, Pennsylvania.

[6] The gap through New York was eliminated in 1928 with a new alignment across the state, crossing the Hudson River on the Bear Mountain Bridge; the old route between Kingston and Port Jervis became the first US 6N.

These routes, which now connected end-to-end at Omaha, replaced a large portion of the Detroit–Lincoln–Denver Highway, which split at Princeton to bypass Chicago to the south via Joliet.

The short stub to Erie, Pennsylvania, formed at the old west end became US 6N, and US 32 remained in Illinois, running independently from Chicago to Princeton and overlapping US 6 to Davenport, Iowa.

The unimproved segment from Ely east to Delta, Utah, about 160 miles (260 km) long, was, according to BusinessWeek, "nothing but a wagon trail-rutted, filled with dust [...] one of the worst chunks of federal road in the country".

[7][17] Starting in early 1983, US 6 was a discontinuous route for almost one year, due to a massive landslide that destroyed the town of Thistle, Utah.