Interstate 20 begins 10 miles east of Kent at the intersection with Interstate 10. From there, the highway travels east northeastward through Odessa, Midland and Abilene before turning eastward towards the Dallas/Fort Worth Metroplex. The La Entrada al Pacifico corridor runs along I-20 between U.S. 385 and FM 1788. Between Monahans and I-10, I-20 has an 80 mph (130 km/h) speed limit, the highest in the United States.
From the highway's opening in the 1960s through 1971, I-20 originally went through the heart of the Metroplex via the Dallas-Fort Worth Turnpike. At that time, I-20 was routed to the southeast west of Fort Worth through the southern sections of Tarrant and Dallas counties. At Mesquite, the highway turned northward, then eastward through Terrell and eastern Texas. This route took the highway over the southern areas of what was once Interstate 820 in Fort Worth and Interstate 635 in Dallas, though I-20 was co-signed with I-635.
That routing of I-20 through the Dallas/Fort Worth area continued until 1987. That year, the highway was rerouted once again, this time from the eastern loop of I-635 and onto a new alignment between Balch Springs and Terrell.
Today I-20 turns to the southeast west of Fort Worth and goes through the southern sections of that city, Arlington, Grand Prairie, Dallas and Mesquite before rejoining its original route at Terrell. Part of I-20 in Dallas is named the Lyndon B. Johnson Freeway.
The original route of I-20 through the heart of the area is now signed Interstate 30 (Dallas-Fort Worth Turnpike), U.S. 80 (former stretch between I-635 and Terrell) and Texas Spur 557 (bypass around Terrell).
Interstate 20 continues eastward from Terrell, bypassing Tyler, Marshall and Longview before crossing the Louisiana border near Waskom.
In Louisiana, I-20 roughly parallels U.S. 80 through the northern part of the state.
Entering the state from near Waskom, Texas, the highway immediately enters the Shreveport-Bossier City metropolitan area, intersecting Interstate 49 near downtown Shreveport and passing close to Barksdale Air Force Base in Bossier city.
From that area, the highway traverses mainly rural, hilly terrain, bypassing Minden, Ruston and Grambling before reaching Monroe.
From Monroe, I-20 enters flatter terrain as it approaches the Mississippi River. Before crossing the Mississippi, the highway passes Tallulah. At the Mississippi River, I-20 leaves Louisiana and enters Vicksburg, Mississippi.
Upon crossing the Mississippi River, I-20 immediately enters Vicksburg. Between Edwards and Clinton, the highway mostly follows the original two-lane routing of U.S. 80. In Jackson, I-20 sees a short concurrency with both Interstate 55 and U.S. 49. Also in Jackson is a fairly low-rise but expansive stack interchange, at the junction of I-20, I-55 North and U.S. Highway 49 South. From the Stack, I-20 continues eastward to Meridian, where it begins the nearly 160-mile overlap with Interstate 59.
The route of the Mississippi section of Interstate 20 is defined in Mississippi Code ¡ì 65-3-3.
Interstate 20 (with I-59) crosses the Alabama line near York and stays conjoined as it passes through Tuscaloosa. At Birmingham, the two highways pass through downtown before splitting at Exit 130 just east of Birmingham International Airport. I-20 continues eastward through Oxford, and the Talladega National Forest, bypassing Talladega Superspeedway in the process, which is visible from the highway.
Also in Birmingham, the intersection of I-20/I-59 and Interstate 65 is known as Malfunction Junction because of the interchange's design and the number of accidents that occur there.
I-20 enters the Peach State near Tallapoosa and immediately enters the Atlanta metro area. On clear days, eastbound motorists get their first view of downtown as they come over the top of Six Flags Hill. In Atlanta, the highway passes through the heart of the city, crossing Interstates 75 and 85 (the Downtown Connector) and continues eastward through the state until it exits the state at Augusta.
Throughout the state, I-20 is conjoined with Georgia Highway 402. However, signs for Highway 402 are not in place. Also, I-20 from the Alabama state line to Interstate 285 in Atlanta is named the Tom Murphy Freeway while it is called the Ralph David Abernathy Freeway within I-285. The highway is also named the Purple Heart Highway from I-285 in Dekalb County to U.S. 441 and the Carl Sanders Highway from U.S. 441 to the South Carolina state line.
Upon leaving Augusta, I-20 crosses the Savannah River and enters the Palmetto State and heads northeastward, bypassing Aiken and Lexington before reaching the state capitol of Columbia, which can be reached most directly by taking I-26 east at Exit 63 ("Malfunction Junction"), then, almost immediately, I-126/US-76.
At Columbia, Interstate 20 bypasses the city to the north and again turns northeastward, bypassing Fort Jackson and Camden. After crossing the Wateree River, it turns due east, passes by tiny Bishopville, before reaching the Florence area. It is near Florence where I-20 sees its eastern terminus at Interstate 95. However, for about two miles, the highway continues into Florence as Business Spur 20.
I-20 in the Palmetto State is known as either the J. Strom Thurmond Freeway or John C. West Freeway. The first section to be completed was the bridge over the Savannah River around 1964, the last, the section between US 401 and I-95 (including the Business Spur), opened in 1974.