U.S. Route 62 runs from the US-Mexico border at El Paso, Texas to Niagara Falls, New York, near the United States-Canada border. It is the only east-west US Route that connects Mexico and Canada.

Parts of U.S. 62 follow what once was the Ozark Trail, including the historic bridge across the South Canadian River in Newcastle, Oklahoma (the first structure built with federal highway funds in Oklahoma).

US 62 has two separate stays in Texas, separated by a portion in New Mexico with the first section in Texas from its terminus in El Paso to the state line in the Guadalupe Mountains. Through El Paso, US 62 begins at the Santa Fe Street Bridge, and follows Santa Fe Street, then Paisano Drive. At the Paisano Drive underpass for I-10 (I-10 exit 23B), US 62 becomes concurrent with U.S. Route 180, while US 180 ends its concurrency with Interstate 10. The route then follows Montana Avenue, continuing the concurrency with US 180 until Seminole. Before exiting Texas, the route passes the southern base of Guadalupe Peak, the highest point in Texas. Through New Mexico, US 62 continues past Carlsbad Caverns National Park into the city of Carlsbad, then east to Hobbs. (NOTE: US 62 west of Carlsbad is being converted into a divided highway through the Texas state line). The highway then crosses back into Texas at the Texas/New Mexico border east of Hobbs, continuing east through Seminole and turning north/northeast through Seagraves and Brownfield into Lubbock along the campus of Texas Tech University's southern border. To the east of Lubbock, US 62 passes through Lorenzo, then forms a spur around Ralls, locally known as the "US 62 Loop". The route then turns north to Floydada, then east through Matador to Paducah, and north again through Childress to a point 17 miles (27 km) to the north where it turns east, forming a concurrency with US 83 before crossing the Texas/Oklahoma border 5 miles (8.0 km) west of Hollis.

US 62 runs east from the Texas border across Southwest Oklahoma through Hollis, Gould and Altus and then continues east bypassing the communities of Headrick, Snyder, Indiahoma and Cache into Lawton, Oklahoma. On the north side of Lawton, US 62 joins Interstate 44 as a concurrent route for 8 miles (13 km) through the Fort Sill Military Reservation and then splits on its own at Exit 46 near Medicine Park to continue north through Apache then north and east toward Anadarko. From Anadarko, US 62 runs east through Verden to Chickasha and northeast through Newcastle before returning to a concurrent route with I-44 into Oklahoma City and then with I-240 and I-35 through much of the city before leaving I-35 at Northeast 23rd Street (Exit 130) two miles (3 km) east of the Oklahoma State Capitol. It leaves Oklahoma City at 23rd street and heads east through Midwest City, Spencer, Nicoma Park, Choctaw, Harrah, Meeker and Boley to Okemah. At Okemah, US 62 overlaps I-40 for 18 miles (29 km) to Henryetta. US 62 then leaves I-40 to continue north to Okmulgee and east to Muskogee, and heads northeast through Fort Gibson and Tahlequah and into Arkansas.

In addition to sections of Interstate highways 44, 240, 35 and 40, US 62 also runs concurrent with other US highways over its miles across Oklahoma including US 281 from Lawton to Anadarko and US 277 from Lawton north about 11 miles (both including the 8-mile (13 km) I-44 concurrency north of Lawton), US 81 in the Chickasha city limits, a second US 277 concurrency from Chickasha to Newcastle, US 75 from Henryetta to Okmulgee, US 64 from an intersection near Taft to Muskogee and US 69 in the Muskogee city limits. US 62 business routes are designated through the cities of Snyder and Muskogee.

Early reports indicated that U.S. Route 62 had "buckled" in three locations and that several nearby homes had major damage. There were also numerous reports of broken windows and other minor damage, mostly to residences.

In the U.S. state of Arkansas, US 62 runs 329.9 miles from the Oklahoma border near Summers east to the Missouri border in St. Francis, serving the northern portion of the state. The route passes through several cities and towns, including Fayetteville, Springdale, Bentonville, Harrison, Mountain Home, Pocahontas, and Piggott. US 62 runs concurrent with several highways in Arkansas including Interstate 540 and U.S. Route 71 between Fayetteville and Bentonville, U.S. Route 412 through much of the state, U.S. Route 65 in the Harrison area, and with U.S. Route 63 and U.S. Route 67 in northeast Arkansas.

Between Malden and New Madrid, US 62 was designated as Route 82 in 1922. The part west of Malden was unnumbered until it became US 62.

U.S. Route 62 overlaps U.S. Route 60 for its entire length, 0.92 miles (1.48 km), in Illinois. It crosses Illinois at its very southern tip between the Mississippi and Ohio rivers. US 62 enters Illinois from Missouri by means of a bridge over the Mississippi River, turning east at U.S. Route 51 with US 51 joining the concurrency. The three routes immediately cross into Kentucky by means of crossing the Ohio River.

U.S. 62 runs right through the tourist section of Western Kentucky including the town of Eddyville, Kentucky and Kentucky Lake and Lake Barkley, two large, man-made lakes. From there U.S. 62 heads east through the towns of Princeton, Central City, Beaver Dam, Leitchfield, Elizabethtown, Bardstown, Lawrenceburg and Midway. For much of this portion, U.S. 62 is paralleled by portions of the Kentucky Parkway System, including the Western Kentucky Parkway (I-69) and the Bluegrass Parkway, which have taken most long-distance and freight traffic off the old U.S. 62 route. After passing through Georgetown and Cynthiana it leaves Kentucky near Maysville. U.S. 62 overlaps U.S. Route 68 in Kentucky to Redoak, Ohio (near Georgetown).

US 62 is the only highway to cross the Ohio River twice. It crosses the Ohio River between Illinois and Kentucky, connecting the far Western region of Kentucky with the Southern tip of Illinois. Its other crossing over the Ohio River connects the Northeastern Kentucky city of Maysville and the Southwestern Ohio village of Aberdeen.

U.S. 62 enters Ohio from Kentucky, crossing the Ohio River at Aberdeen. It crosses southwest Ohio before entering the cities of Columbus, Canton, Alliance, and Youngstown. It leaves Ohio near Hubbard and enters Pennsylvania near the interchange for Interstate 80.

U.S. 62 is planned to be rerouted onto a divided highway from Alliance to Salem, part of a larger relocation of both U.S. 62 and SR-14, then from downtown Youngstown to Interstate 80 as part of the "Hubbard Arterial". Parts of the highway have long been completed to the north of Alliance and Salem; the portion northwest of Alliance is known in documents as US-62T, while the portion north of Salem not already carrying U.S. 62 is known as SR-14T; neither carries a posted route, instead only carrying trailblazer markers indicating routes intersected at the termini.

U.S. 62 enters Pennsylvania from Ohio in Sharon. Also, at the Ohio/Pennsylvania state line, signage for U.S. 62 changes from an east–west to north–south. U.S. 62 also runs north-northeast from the Ohio border towards New York. U.S. 62 passes through Mercer and runs across country to Franklin. At this point U.S. 62 enters the Allegheny River valley and follows this river for 45 miles (72 km). U.S. 62 crosses the river at Oil City, at Tionesta, and twice again in the Warren area, once near Buckaloons Recreational Area in the Allegheny Islands Wilderness region, where it is concurrent with U.S. Route 6 for a short distance.

While most of the route is an east–west route, US 62 takes a north–south directionality in Pennsylvania and New York. It is signed north–south in northern Pennsylvania and New York.

US 62 enters New York State from Pennsylvania in Chautauqua County, south of Frewsburg, past which it intersects with Interstate 86 (Southern Tier Expressway). Following a northeasterly course, US 62 enters Cattaraugus County, crosses Cattaraugus Creek to enter Erie County and passes through the village of Gowanda, taking a more northerly direction. At the village of Hamburg, US 62 turns northeast, passing Buffalo Raceway and the Erie County Fair, New York State Thruway (Interstate 90), continues northward through Lackawanna as South Park Avenue and passes through Buffalo as South Park Avenue and Bailey Avenue. The Bailey Avenue section from NY 5 at the Buffalo city line to NY 324 is maintained by Erie County as CR 152.

US 62 briefly overlaps New York State Route 324 (Sheridan Drive) in the town of Amherst, and turns northward as Niagara Falls Boulevard, intersects Interstate 290, then exits Erie County and enters Niagara County, as US 62 crosses the Erie Canal / Tonawanda Creek and travels into the town of Wheatfield. The highway intersects New York State Route 425 and turns to the northwest intersecting New York State Route 265 and Interstate 190. On the east side of Niagara Falls the route diverges into US 62 and its parallel route, Business U.S. Route 62, (formerly NY 62A). Within the city of Niagara Falls, US 62 runs "backwards", bearing west for several miles as Ferry Avenue southbound (eastbound) and Walnut Avenue northbound (westbound) and terminates on Main Street, while is still signed north–south. The northern (eastern) terminus for both US 62 and Business US 62 is at New York State Route 104, or Main Street, less than 2,000 feet from the Rainbow Bridge and U.S. Customs. The Rainbow Bridge then crosses the Niagara River into Canada, offering side-views of the famous Niagara Falls.

US 62 has bannered and suffixed routes in several states.

List of unused highways in Ohio

^ Ohio Department of Transportation Straight Line Diagrams for Columbiana and Mahoning Counties