In addition to Tulsa, US-64 serves fifteen Oklahoma counties and the cities of Guymon, Woodward, Enid, and Muskogee.

US-64's route has remained roughly the same since then, although it has undergone alterations several times, mainly changing its course through towns and moving the highway designation to higher-capacity expressways and freeways.

The three highways enter the state just north of the extreme southwest corner of Cimarron County, the westernmost tip of the Oklahoma Panhandle.

About four miles (6.4 km) east of the county line, US-64 reaches the town of Turpin; here, the highway begins a concurrency with US-83.

US-83 and westbound US-270 continue north from this junction toward Liberal, while US-64 and US-270 eastbound form a concurrency heading due east.

East of Forgan lies a highway junction with SH-23—here, US-270 splits away from US-64, turning south along SH-23 en route to the county seat, Beaver.

[7] Three miles (4.8 km) east of Gate, the highway crosses the Beaver–Harper county line, the eastern boundary of the Oklahoma Pandhandle, and enters the main body of the state.

The two routes part ways northeast of town, with US-183 continuing on a northerly course toward Kansas and US-64 turning east once again.

About 2+1⁄2 miles (4.0 km) east of the junction, the two highways cross the Cimarron River, which forms the northeastern boundary of Harper County.

US-64 continues on east, passing through unincorporated Plainview and turning southeast to intersect SH-50 at its northern terminus at Camp Houston, north of Freedom.

This concurrency lasts about one mile (1.6 km) before US-281 splits off to the north on the east side of town; at this point, SH-14 ends.

This street has a parclo interchange with Owen K. Garriott Road, which carries US-412; here, US-64 joins US-412, and the two highways head due east out of Enid as a four-lane expressway.

The two highways head southeast out of town together for just over two miles (3.2 km) before SH-18 splits off to the south toward Lone Chimney.

This portion of the highway runs parallel to Keystone Lake, a reservoir formed by the impounded Arkansas River.

[4] US-64 / US-412 continue east from the eastern terminus of the Cimarron Turnpike in southeastern Pawnee as a freeway known as the Keystone Expressway.

Here, the highway serves as the southern limit of Westport and Mule Barn, which remains an incorporated town despite having a population of zero.

[13][14] The freeway turns southeast, briefly entering Westport before crossing Lake Keystone into Osage County.

The freeway passes through an outlying parcel of Sand Springs, running parallel to the Arkansas River, before emerging into unincorporated territory.

Proceeding east, the freeways re-enter Sand Springs, passing through an interchange with SH-97 just south of downtown.

[17] The Keystone Expressway continues to an interchange at the northwest corner of the Inner Dispersal Loop (IDL), a ring of freeways encircling downtown Tulsa.

On the southern outskirts of Bixby, it turns east, passing through unincorporated Leonard before exiting Tulsa County.

Approximately 2+1⁄2 miles (4.0 km) south of the county line, the highway serves the town of Haskell, where it begins a concurrency with SH-72 and junctions with SH-104 at its western terminus.

US-64 turns back to the east here, running parallel to I-40 between Warner and Webbers Falls, where it has an interchange with the Muskogee Turnpike.

The two highways pass northwest of downtown Webbers Falls before crossing the Arkansas River, which forms the boundary of Muskogee County, a third time.

On February 19, 1934, the Oklahoma Highway Commission approved the re-routing of US-64 onto a roadway a bit further west to eliminate these turns.

[24][25] On July 7, 1947, another modification to the route was made, moving its western terminus from the northern portion of the panhandle to a new roadway in the southern section.

[29] Later, on December 1 of the same year, similar reroutings through Tulsa and Broken Arrow were approved by the Oklahoma Department of Highways.

[35] The next and final major modification to the designation of US-64 took place when it was moved from its route through eastern Tulsa onto the newly constructed Creek Turnpike over the first half of 1992.

[24] The section of US-64 between Webbers Falls and Gore was pressed into service as a detour for I-40 traffic after the collapse of its bridge over the Arkansas River on May 26, 2002.

State Highway 64A began at I-35 exit 186 and extended east into Perry for approximately two miles (3.2 km).