The freeway mainly spans rural areas and passes numerous small towns along its route, including Fulton, Tupelo, New Albany, and Holly Springs in Mississippi and Jasper, Winfield, and Hamilton in Alabama.

I-22 serves as a connection between Birmingham and suburban Memphis, filling in a gap in the Interstate Highway System.

[3] It begins at an interchange with I-269 at Byhalia, Mississippi, approximately 25 miles (40 km) from downtown Memphis and travels southeast across northern Mississippi and Alabama, before ending at an interchange with I-65 approximately five miles (8.0 km) north of downtown Birmingham, Alabama.

[citation needed] I-22 begins at a cloverleaf interchange with I-269 just west of Byhalia in DeSoto County in northwestern Mississippi in the far southeastern suburbs of Memphis.

It is concurrent with US 78, which is a four-lane freeway through its entire length in Mississippi and the exit numbers for its overlap with I-22 remain based on its mileage.

To the southeast of the city near the town of Sherman in Pontotoc County, I-22/US 78 has a second brief concurrency with MS 9 starting between the exits 73 and 76.

The freeway then turns eastward and has an interchange with MS 371 north of Mooreville before crossing into Itawamba County.

[citation needed] Still a four-lane freeway, I-22/US 78 (internally designated as State Route 4, or SR 4) enters into northwestern Alabama northwest of Bexar in Marion County and heads east-southeastward.

I-22 than passes through Coalburg before ending at an interchange with I-65 (unsigned exits 95A and 95B) approximately five miles (8.0 km) north of downtown Birmingham.

Ramp stubs for an additional interchange (future exit 95C) just beyond I-65 to US 31 have been made, but construction on this won't begin until at least 2030.

[8] In Alabama and Mississippi, blue signs reading "FUTURE/I-22/CORRIDOR" at left and an I-22 shield with "FUTURE" instead of "INTERSTATE" at the right were unveiled on April 18, 2005.

[8] The first major completed section of the route between the Mississippi state line and Jasper was opened to traffic on November 22, 2005.

[9] Exits on the Jasper Bypass portion of I-22 were originally numbered using a kilometer-based sequence because, at the time this stretch was opened, it appeared that all highways in the US were going to be measured using the metric system.

[12] The Alabama Department of Transportation (ALDOT) widened Coalburg Road from its interchange with I-22 southward to Daniel Payne Drive (which leads to I-65) to allow heavy trucks to use it; this project was nearly complete as of May 2015.

This extension gave the ALDOT the opportunity to proceed with its plans for the construction of final segment of I-22 in Alabama.

[16] On November 12, 2012, ALDOT's application for establishing I-22 was conditionally approved by the American Association of State Highway and Transportation Officials (AASHTO) at a special committee, pending for the Mississippi Department of Transportation (MDOT) to submit their own application for I-22 and Federal Highway Administration (FHWA) approval.

[17] In April 2013, the first actual I-22 shields were deployed in Marion County, Alabama, immediately east of the Mississippi state line.

New lanes north and southbound were opened on I-65 passing through the interchange and construction and painting operations were carried out on the I-22 entrance and exit ramps.

A complaint has been filed over construction resuming,[30] and although ALDOT expected to break ground on the resumption of the project in November 2023, no new information was made public for several months.