
The museum is housed in the former site of the Dothan Municipal Light and Water Plant, the building and grounds of which are listed in the 1991 National Register of Historic Places. The city of Dothan established the plant in 1913 to provide electricity and water to its growing population. It served Dothan's increasing needs until 1949, when the plant was shut down and the city began purchasing all of its electricity from Alabama Power Company. The museum complex is located next to Dothan's Main Street Commercial Historic District.
In 1987, the Dothan City Commission passed an ordinance establishing a museum board of directors. The museum initially housed its collections by renting space in the local malls in 1989 until the city of Dothan authorized the use of the old municipal power plant as its future location. A master plan to renovate the building was developed by the architecture firm of Donofro and Associates, and the renovated facility opened its doors in 1991.
The museum houses a permanent collection of more than 500 art objects focusing on American and southern fine, decorative, and design arts from 1945 to the present; American works on paper from 1945 to the present; and specifically Alabama artists and women artists. Notable works in the museum's collection include a bronze by John Singer Sargent, lithographs by Alexander Calder and Ellsworth Kelly and several pieces by renowned contemporary artist Frank Stella including Jonah Historically Regarded, La penna di hu, and Sinjerli Variation Squared with Colored Ground II 11/29. Also among the artists represented are several pieces by internationally recognized local artist Dale Kennington, including At the Corner of Walk and Don't Walk.

Since its opening, the Wiregrass Museum of Art has continued to build and expand. As of 2009, the museum had completed three of four phases of a construction plan. The first three phases created 18,000 square feet of gallery space, an exhibit preparation area, a vault, and the conference center. The fourth phase includes the construction of a new educational wing and a new entrance.