State Highway 66 begins at Business I-40 in El Reno (another old Route 66 segment), concurrent at this point with US-81.

The highway briefly passes through a rural area after leaving El Reno, before transitioning into the Oklahoma City suburb of Yukon.

39th Expressway, still carrying SH-66, forms the main street of both Bethany and Warr Acres, two enclave suburbs of Oklahoma City.

The street passes just to the south of Wiley Post Airport and provides access to Southern Nazarene University.

I-44, while concurrent with SH-66, runs along the north side of Oklahoma City, passing just south of Penn Square Mall, and meets Interstate 235 at a cloverleaf interchange at its northern terminus (north of the interchange, US-77 continues on as a freeway, the Broadway Extension).

The two interstates and the state highway head north through the northeast part of the city.

The highway then passes through the town of Arcadia, home of the Round Barn, a Route 66 landmark.

East of this junction, SH-66 passes through the town of Warwick, where it crosses the Deep Fork of the Canadian River.

[6] Seven miles (11 km) east of Chandler, the highway passes through the town of Davenport.

[4] The route next encounters Stroud, where SH-66 intersects State Highway 99 and US-377, which may serve as the northern terminus of US-377.

The highway passes through the town of Depew 10 miles (16 km) northeast of Stroud.

The highway crosses the Turner Turnpike again (with no interchange this time), then runs through Kellyville.

The two highways intersect SH-117A at its northern terminus, and turn left to continue its alignment.

US-75 ALT/SH-66 parallel the Turner Turnpike within sight distance for the remainder of their journey in Creek County.

The next town that SH-66 serves after leaving the Tulsa area is Claremore, seat of Rogers County.

The highway continues northeast through Rogers County, bypassing Sequoyah to the west and serving as the western terminus of SH-28A in Foyil.

[4] The route then crosses into Craig County, where it serves the unincorporated place of White Oak.

Planned improvements by the Oklahoma Department of Transportation include reconstruction and widening of SH-66 from two to four lanes from Edmond to the Lincoln County line.