The highway crosses into the state from Texas west of Arnett and serves many towns and cities in the northern part of the state, including Arnett, Seiling, Fairview, Enid, Ponca City, Pawhuska, Bartlesville, and Vinita.

The first 60.2 miles (96.9 km) of the route, from the Texas line to Seiling, is also designated as State Highway 51 (SH-51).

[3] The highways head due east from the state line for seven miles (11 km) before coming to an intersection with US-283.

On the north side of town, US-270 and SH-3 continue to the northwest, while US-60 and US-281 take a more northerly tack that will take them towards Major County.

[4] US-60 then passes through a series of unincorporated locations: Orion, Bado, Dane, and Cedar Springs.

[5] In downtown Enid, US-60 turns off of Garriott and onto Van Buren Street, leaving US-412 and joining US-81 instead.

Fourteen miles (23 km) north of Enid, the three routes come to a T junction; US-64 turns west here, while US-60 and US-81 head east.

[4] After four miles (6.4 km), the highways come to the town of Pond Creek; here US-81 splits off towards the county seat of Medford and on to Kansas.

[4] US-60 continues east, crossing the Salt Fork of the Arkansas River and briefly concurring with SH-74 to the west of Lamont, where the two part ways.

East of I-35, US-60 begins a concurrency with US-77; this interchange is also the western terminus of US-60 Business, which serves downtown Tonkawa.

US-60 does not have another junction with a state highway for 21 miles (34 km), when it comes to an intersection with SH-11 and SH-18 southeast of Burbank.

[9][7] After only 0.2 miles (0.32 km), US-60 turns to the east along Adams Boulevard, splitting away from SH-123, and fully enters Washington County.

At this interchange, US-60 turns south and overlaps US-75 before splitting off to the east once again, leaving Bartlesville and, soon, Washington County behind.

[10] Three miles (4.8 km) east of Nowata,[4] the highway passes through unincorporated Coodys Bluff, where it crosses the Verdigris River.

[7] US-60's first highway junction in Craig County is at the eastern terminus of SH-66 east of the incorporated location of White Oak.

Just outside Vinita, US-60 has its first interchange with I-44, which is also carrying the Will Rogers Turnpike at this point (this is US-69's second I-44 junction; it previously intersected I-44 near Big Cabin).

Less than a mile north of the US-59 junction, the three highways pass through a cloverleaf interchange; proceeding north through this interchange places a motorist on US-59/US-69 bound for Miami, heading west leads to the toll booth for I-44, and turning east puts the motorist on US-60 eastbound.

[7][12] US-60, now with no other highways concurrent with it, will parallel the BNSF rail line for the remainder of its time in Oklahoma.

On May 29, 1930, AASHO approved an extension westward to Amarillo, Texas, bringing the route through Oklahoma for the first time.

[5] On October 22, 1936, a section of US-60 and SH-48 (the precursor to SH-99 in that area) in Osage County north of Pawhuska was abandoned in favor of a new alignment that led to a new grade separation.

The highway was adjusted through Fairland to use Connor Avenue, a shorter, straighter route through town; this change was approved on July 11, 1949.

[21] Further west, US-60 and US-177 were realigned in Tonkawa on May 4, 1953, replacing an alternate US-60/US-177 that previously paralleled the main highway there.

The new (present-day) alignment of US-60, approved December 17, 1956, instead diverged at an interchange also serving the Will Rogers Turnpike, then headed northeast to Fairland.

[30] On April 3, 1967, the Oklahoma Highway Commission approved a realignment of a short segment of US-60/US-64/US-81 north of Enid in Garfield and Grant Counties.

[31] AASHO received applications for both the Burbank and Enid-area relocations on April 24 and approved both of them at the organization's June 20 meeting.

This change was submitted to AASHO, now renamed to AASHTO, on April 29, 1975, received on May 1, and approved on June 17.

While the two highways still passed through Pawhuska from west to east, after turning north, the new route bypassed much of the city.

The application for this alteration was submitted to AASHTO on September 22, received the same day, and approved on November 8.

On March 19, 2001, 0.73 miles (1.17 km) US-60 and SH-51 west of Arnett were moved slightly to connect to a new bridge.