Western Alabama

After I-20/I-59 enters Alabama from Mississippi, they travel concurrently northeastward across the Tombigbee River and Black Warrior River delta country which is generally low-lying farmland until reaching Tuscaloosa. This area contains low population. U.S. Route 11 (US 11) parallels this route from Mississippi northeastward while it passes through small towns like York, Livingston, and Eutaw before reaching Tuscaloosa. From the Mississippi–Alabama state line to Tuscaloosa, I-20/I-59 is a four-lane route.

At Tuscaloosa, the highway connects with I-359 which travels northward into downtown Tuscaloosa and to the University of Alabama. After the I-359 junction, the route widens to become six lanes. From Tuscaloosa to Birmingham, the highway continues on an east-northeast heading traveling through rolling forested terrain until reaching I-459 southwest of Bessemer. All of the stretch from Tuscaloosa to the I-459 junction near Bessemer is six lanes. 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. I-422 (Birmingham Northern Beltline) is slated to connect to I-20/I-59 at the I-459 interchange; however, this project is still years away from completion.

I-20/I-59 approaching Birmingham in Ensley

I-20/I-59 approaching I-65 in downtown Birmingham before the section of highway was rebuilt in 2019. This was sometimes referred to locally as Malfunction Junction.

Birmingham

After passing the I-459 interchange, the highway continues northeast as a four-lane highway through the Birmingham suburbs of Bessemer, Hueytown, and Fairfield before widening after exit 118 in Fairfield to at least six lanes as the interstate approaches Birmingham near the Ensley community. Most of this stretch is through urban areas including passing near the U.S. Steel plant near Fairfield, and visible from the Interstate looking north and northwest are several smokestacks which is all that remain of several large steel mills that used to dominate the Ensley community of Birmingham.

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").

As I-20/I-59 leaves the downtown area, the highway has an interchange with the Elton B. Stephens Expressway, also known locally as the Red Mountain Expressway, which travels south across the downtown area and into the southern Birmingham suburbs.

The highway continues east-northeast through downtown before reaching the Birmingham–Shuttlesworth International Airport where I-59 continues northeast toward Gadsden and I-20 turns eastward toward Atlanta.

Once I-20 turns away from I-59, it begins an eastbound journey toward Georgia. 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.

I-20 is a six-lane freeway from exit 132 to exit 162. This highway travels through rolling suburban country and crosses I-459 near Irondale.

"Bloody 20"

The section of I-20 between Leeds and Pell City was one of the most dangerous stretches of Interstate Highway in Alabama. The terrain is significantly hilly as the route passing across the northeast to southwest ridges of the Appalachian Mountains. There are two significant uphill grades in each direction which slows down truck traffic. However, due to the heavy volume of truck traffic combined with speeding car traffic, accidents were frequent and sometimes deadly. This part of I-20 was sometimes called "Bloody 20". Between 2010 and 2014, work was completed to add one additional lane in each direction along I-20.

Eastern Alabama

The highway continues as a six-lane highway until reaching the Coosa River bridge near Riverside. This bridge was scheduled to be replaced when the stretch between the Coosa River and milemarker 172 is widened to six lanes from four lanes. However, no timetable for this project has been announced. Exits 165 and 168 serve the Honda Motor Company which has a plant at Lincoln. Exits 168 and 173 serve the Talladega Superspeedway which hosts two NASCAR racing weeks each year. The terrain east of milemarker 155 until reaching milemarker 191 is the relatively flat Coosa River valley.

SR 202 at I-20 at exit 179

East of milemarker 172 until milemarker 188, the route is once again six lanes. From exit 188 to exit 205, I-20 narrows again to four lanes. East of exit 205, I-20 becomes a six-lane route until it reaches exit 210. However, in this area, construction is ongoing to widen the last five miles (8.0 km) to six lanes to the Georgia state line. I-20 dives into Oxford from the west into its interchange with Alabama State Route 21 (SR 21). Here, you can see Quintard Mall and some of the highest mountains in Alabama, including Cheaha Mountain. The Anniston–Oxford metropolitan area is served by exits 179, 185, 188, and 191.

Just east of exit 191 is a significant uphill/downhill grade (uphill eastbound/downhill westbound) approximately two miles (3.2 km) long. Truck traffic is significantly slowed by this hill, causing occasional traffic backups. 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.

This stretch of Interstate contains multiple parclo Interchanges.

East of Birmingham, US 78 serves as the parallel U.S. Route.