At Birmingham, I-20 turns eastward and heads through Oxford before crossing the Georgia state line near Lebanon.

From Tuscaloosa to Birmingham, the highway continues on an east-northeast heading traveling through rolling forested terrain until reaching I-459 southwest of Bessemer.

This stretch also hosts the Mercedes auto plant which is a large employer of residents primarily from Jefferson, Tuscaloosa, and Bibb counties.

I-459 travels east and then northeast around the southern periphery of the Birmingham area before reconnecting first with I-20 near Irondale and then terminating at I-59 near Trussville.

As I-20/I-59 travels eastward just past the Arkadelphia Road exit in the East Thomas community, the highway rises to the top of East Thomas hill, giving eastbound travelers an excellent view of the downtown Birmingham skyline just before reaching the interchange with I-65 (commonly called "Malfunction Junction").

The first two miles (3.2 km) are a four-lane bridge of east Birmingham neighborhoods before reaching the shopping areas formerly known as Eastwood Mall and Century Plaza.

The terrain is significantly hilly as the route passes across the extreme southern end of the Appalachian Mountains.

However, in this area, construction is ongoing to widen the last five miles (8.0 km) to six lanes to the Georgia state line.

Just east of exit 191 is a significant uphill/downhill grade (uphill eastbound/downhill westbound) approximately two miles (3.2 km) long.

East of this incline, the route travels through generally rural forested rolling country until the Georgia state line, continuing roughly 50 miles (80 km) to Atlanta.

The next section of I-20 to open in Alabama was a four-mile-long (6.4 km) stretch between Avenue I in Ensley and Arkadelphia Road (US 78/SR 5) near Birmingham–Southern College.

The opening of additional segments continuing eastward led to temporary ends of I-20 at SR 79 (Tallapoosa Street) near Birmingham–Shuttlesworth International Airport, then at US 78 in Irondale.

The final segment of the route to be completed was an eight-mile-long (13 km) section between Irondale and Leeds.

The closing of the base as well as a lack of population between Anniston and Gadsden eliminated the necessity of such a route.

I-459 south of Birmingham connects to I-20 east and west of the city, continuing to I-59 northeast of the routes' split.