The highway connects Mobile, the largest city in South Alabama, with Pascagoula, Mississippi, to the west and Pensacola, Florida, to the east.

I-10 continues east-northeast through a partial cloverleaf interchange with County Road 39 (CR 39) north of Irvington.

The highway has a directional-T interchange with the southern end of I-65, which serves Montgomery and Birmingham.

I-10 continues northeast from I-65 as an eight-lane freeway that parallels CSX's NO&M Subdivision rail line.

Within that interchange, the freeway reduces to four lanes and curves east and descends into the George Wallace Tunnel to pass under the Mobile River.

The dual viaducts reach the eastern shore just west of a five-ramp partial cloverleaf interchange with US 90 and US 98 south of the center of Spanish Fort and north of Fairhope.