Luton came from behind to record their first win of the season.
Jonathan Brown gave the visitors an early lead but Adam Watkins finished neatly to level for Luton.
Southport's Steve Akrigg was sent off for a second yellow card, before Will Antwi tapped in Dean Beckwith's header to put the Hatters ahead.
Amari Morgan-Smith's deflected effort made it 3-1, with Robbie Willmott's spectacular 25-yard strike and Danny Crow's header completing the rout.
Luton: Tyler, Osano, Antwi, Beckwith, Howells, Keane, Lawless, Willmott, Dance (Crow 31), Watkins (Asafu-Adjaye 79), O'Connor (Morgan-Smith 60).Subs Not Used: Kevin Pilkington, Barnes-Homer.
Booked: Keane, Beckwith.
Goals: Watkins 41, Antwi 71, Morgan-Smith 73, Willmott 77, Crow 78.
Southport: McMillan, Smith, Akrigg, Grand, Lever, Lee, Whalley, Brown (Osborne 72), Ledsham, Kissock (Benjamin 46), Gray (Owens 72).Subs Not Used: Nemes, Ordish.
Sent Off: Akrigg (68).
Goals: Brown 8.
Ref: Alun-Wyn Davies (Southampton).