From Slidell, I-59 heads northeast, passing very close to Pearl River before crossing both the west and east branches of the Pearl River. At the East Pearl River, I-59 leave Saint Tammany Parish and enters Pearl River County, Mississippi.
In the Magnolia State, I-59 continue to parallel U.S. 11 through mainly rural areas, going through or bypassing Picayune, Hattiesburg, Laurel and Meridian.
Near Laurel, I-59 features two sharp curves with posted speed limits of 40 miles per hour (60 km/h), one of the slowest on the interstate system. After more than 20 years of trying, the Mississippi Department of Transportation is currently in the midst of a $36 million project to straighten out the dreaded curve.
At Meridian, Interstate 20 joins I-59 and the two highways continue together for 145 miles to the Alabama border and beyond to Birmingham.
At 4:00 p.m. on August 27, 2005, for the first time in its history, the southbound lanes of Interstate 59 were temporarily redirected northward to accommodate evacuation for Hurricane Katrina. This was a previously agreed to joint plan by the states of Mississippi and Louisiana called Contraflow lane reversal. The program began at the Mississippi-Louisiana state border and continued 21 miles (33 km) north to Poplarville.
Interstates 59 and 20 are conjoined for much of their route through Alabama, passing northeastward through Tuscaloosa before finally parting ways in eastern Birmingham.
In Birmingham, many wrecks and accidents occur near the interchange of I-20/59 and Interstate 65. On two occasions, 18-wheelers crashed and burned fiercely enough to melt the support beams of overpasses. Because of the frequent and severe wrecks, this interchange is nicknamed "Malfunction Junction". From Birmingham, I-59 continues northeastward near Gadsden and Fort Payne before entering Georgia.
Interstate 59 has a very short trek through the Peach State, having only three exits before coming to an end at Interstate 24 several miles west of Chattanooga, Tennessee in Wildwood. During the entire length, the highway is designated State Route 406 but is not signed as such.