Andre Green's fine finish put Villa 1-0 up on 24 minutes at Staplewood, before Harry McKirdy converted a penalty and set up Aaron Tshibola to slot in the visitors' third on 39 minutes.
Sam McQueen gave Saints hope with a low drive just before half-time, but captain Easah Suliman hit a fourth for the visitors late on.
Villa are on 27 points, ahead of second-placed Middlesbrough because they have scored more goals, while third-placed Reading are only behind on goal difference. Southampton remain ninth.
Saints: 22 Jan v Watford (A) PL Cup
Villa: 22 Jan v West Brom (A) PL Cup