[citation needed] As of 2020[update], the highway's eastern terminus is in Columbia, Tennessee at an intersection with Interstate 65, where it continues east as State Route 99.

Cities along the route include Siloam Springs, Springdale, Alpena, Harrison, Cotter, Mountain Home, Salem, Walnut Ridge, and Paragould.

[5] Now named Sunset Avenue, the route passes through developed parts of Springdale, including many restaurants, hotels, and businesses before turning south, forming a concurrency with US 71B.

The concurrency ends and US 412 heads east past the Springdale Municipal Airport and Highway 265 out of town.

[7] The highway passes the James C. Chaney House and Stamps Store in Osage, the Dog Branch School, and the Yell Masonic Lodge Hall in Carrollton.

[8] This overlap is approximately 150 miles (240 km) through many north central Arkansas communities, including Harrison, Cotter, Mountain Home, Ash Flat, and Hardy.

Further east, the route intersects I-57/US 67 at a full interchange before crossing the Cache River and entering Greene County.

U.S. 412 crosses the Missouri Bootheel, and runs concurrent with Interstate 155 east of Hayti to the Tennessee state line.

The interstate designation ends as 412 turns southeast toward Jackson on a stretch of highway that was upgraded from 2 to 4 lanes in the 1990s.

After leaving Jackson on its eastern side, US 412 passes through the towns of Lexington, Parsons, and Hohenwald before reaching Columbia.

Charles Gibson piloted the ferry on that trip, carrying three cars across the lake within the shadow of the bridge, which brought a 40-year era to an end.

The senators' stated reasons for seeking an Interstate designation along the US-412 corridor included encouraging economic development, expanding opportunities for employment in the region, making travel safer and shipping easier, attracting new businesses, and better connecting rural and urban communities.

[16] In October 2023, officials from both states requested public feedback on the US 412 study area, which is approximately 190 mi (310 km) long.