Duke's announcement came Friday on his website.
I am Running for U.S. Senate Watch the video! https://t.co/mOvc4CaPfx— David Duke (@DrDavidDuke) July 22, 2016
A registered Republican, he would be seeking an open seat vacated by Republican David Vitter.
Duke's announcement comes as Louisiana is grappling with deep racial tensions after the shooting death of a black man by white police officers and the killing of three law enforcement officers by a black man.
A white supremacist, Duke served one term as a state representative representing suburban New Orleans more than two decades ago. He ran unsuccessfully for governor in 1991 against Democrat Edwin Edwards.
Duke is a convicted felon, pleading guilty in 2002 to bilking his supporters and cheating on his taxes. He spent a year in federal prison.