The 2021 Southern Miss Golden Eagles football team represented the University of Southern Mississippi in the 2021 NCAA Division I FBS football season. The Golden Eagles played their home games at the M. M. Roberts Stadium in Hattiesburg, Mississippi, and competed in the West Division of Conference USA (CUSA). They were led by first-year head coach Will Hall.
On October 28, 2021, Southern Miss announced that this will be the last season for the team in the C-USA and will join the Sun Belt Conference on July 1, 2022.
The Golden Eagles were predicted to finish in fourth place in the West Division in the Conference USA preseason poll.