Salem was first settled in 1835, and grew rapidly for the next two decades. Salem incorporated in 1846 and quickly became one of the area's largest cities. However, a fire which engulfed the town in 1854 and the subsequent Civil War resulted in the collapse of the town's government, and rapid depopulation. Salem lost a bid to be the county seat of the newly formed Lee County in 1865, and then saw its charter become inactive in the following decades. Today, Salem is a small community of a few hundred.
By the late 20th century Salem was the location of Lee County's only covered bridge, the Salem-Shotwell Covered Bridge. A symbol of the area, the bridge was destroyed by a fallen tree following a storm in 2005. It was rebuilt in 2007 at Opelika Municipal Park in nearby Opelika.
On Saturday February 28, 2009, around 8:30 AM, an EF2tornado touched down in Salem, destroying Salem Chapel AME church, several homes, and part of Wacoochee Junior High School. It Also destroyed the Anglican, Church of the Resurrection, ACA Mission located right in the middle of down town Salem. The Church was completed in 2008 in the building that most people knew as the old McLain Museum. This building had been used for several other businesses over many years it stood and will be a great void in the Salem area. The tornado ran east-northeast across part of U.S. Highway 280, which runs through the small community, before lifting up two miles to the east. There were no fatalities and no major injuries reported.