The route runs 75.60 miles (121.67 km) from US 64 in Fort Smith east to Highway 7 in Dardanelle.

Following the historic stagecoach line of the cross-country Butterfield Trail, the route is one of the original 1926 state highways.

It runs east, crossing I-540/US 71 and the incomplete interchange at the northern end of Highway 549 (future I-49).

[2] From its western terminus in Fort Smith, it carries the Seminole route of the Trail of Tears to Highway 255.

[11] In June 2019 a proposal was made under the Connecting Arkansas Program-2 for US$25 million to be allocated to the improvement of sections of Highway 22 between Fort Smith and Charleston.

[12] On March 20[13] of the same year, the highway was officially designated by the AHTD as the True Grit Trail.

[14] Three original segments of Highway 22 remain intact and are listed on the National Register of Historic Places.

Now named Mayo Drive, it consists of a 0.5-mile (0.80 km) stretch of concrete pavement, two lanes wide, in the northwestern part of the city.

It consists of an S-shaped section asphalt, 1.5 miles (2.4 km) in length, built in 1930 by Cook & Ransom and the Schultz Construction Company to carry Highway 22.