US 166 meets the old route of US 66, now designated US 69 Alternate, in Baxter Springs in the southeast corner of Kansas.

Traveling 50 miles (80 km) east of Arkansas City, US 166 turns northeast, arcing above Cowley County Lake Dam and Cedar Vale.

166 crosses the Caney River approximately 0.5 miles (0.80 km) east of Chautauqua County Road 2.

It turns south of Sedan approximately 0.6 miles (0.97 km) east of Chautauqua County Road 14.

It then proceeds northeasterly past Walter Johnson Park and the Montgomery County Fairgrounds before it crosses the Verdigris River.

US 166's eastern terminus is its interchange with I-44, 0.6 miles (0.97 km) from the state line[1] and about 1,000 feet (300 m) from the Oklahoma–Kansas–Missouri tripoint.

In 1966, following the completion of the last section of I-44 in Missouri, the east end of US 166 was truncated back from Springfield to its current terminus.

In a resolution on December 22, 1993, KDOT approved and requested to realign US-166 south of Sedan, and to re-designate the former alignment as US-166 Business.

In a December 22, 1993 resolution, KDOT approved and requested to realign US-166 south of Sedan, and to re-designate the former alignment as US-166 Business.