The 24-year-old winger has scored four goals in 74 appearances since joining the Premier League club from Standard Liege in 2019.
“It is proof of the club’s trust in me, so I say thank you for everything,” he told the club website.
“It’s the team I want to grow up with and learn more, and I will give my best to do everything for the club.”
Southampton boss Ralph Hasenhuttl described Djenepo as “a fantastic character” and “a very popular player in the dressing room”.
Djenepo made his Mali debut in a World Cup qualifier against Ivory Coast in October 2017, and has scored three goals in 29 outings for the Eagles.
His new deal will keep him at St Mary’s until the end of the 2024-25 campaign.