The highway parallels US Route 90 (US 90) to the north, traversing the southern parts of the three southernmost counties in the state: Hancock, Harrison, and Jackson.

It widens from four to six lanes between the bridge over the Wolf River and exit 28 (Country Farm Road) northeast of Cuevas.

The highway passes through the northern section of Mississippi's second-largest city, Gulfport, and has a cloverleaf interchange with US 49 (exit 34) crossing a railway line, US 49 itself, and Bayou Bernard in the process, respectively.

[2] Four miles (6.4 km) later, I-10 intersects MS 605 (Lorraine Road), which provides access to Gulfport's eastern neighborhoods and crosses the Biloxi River.

The first westbound truck weigh station can be spotted across the road before I-10 finally enters Alabama after trekking 77 miles (124 km) in the Magnolia State.

Today, entering Mississippi from Louisiana, the first 12 miles (19 km) is the NASA John C. Stennis Space Center easement zone.