A couple of braces from James Wilson - who was celebrating his 17th birthday - and Mats Daehli sealed a deserved win at Carrington despite Saints rallying late on.
Wilson put United in front on 21 minutes with a superb volleyed finish from Adnan Januzaj's left-wing free-kick.
Januzaj was the creator once more eight minutes later when he put Daehli through on goal and the Norwegian finished with aplomb.
Sixty-five seconds later though, the visitors pulled one back through Gboly Ariyibi who tucked home a low cross from close-range.
Just after Wilson had seen a well-struck effort come back off the post, the Reds regained their two-goal cushion two minutes before the break as Januzaj and Daehli combined brilliantly again with the former supplying an inch-perfect pass for the latter to steer home.
Wilson made it 4-1 on 65 minutes after rounding the goalkeeper and slotting into an empty net. Southampton were given a lifeline ten minutes later when Fraser Colmer headed home from a corner, but the Reds held out to ensure a triumphant end to their Group Two campaign.
United: Sutherland; Grimshaw, Dalley, Ioannou, Evans; Weir, Pearson (Rothwell 68), Rudge (Barmby 46), Daehli (Gorre 64); Januzaj; Wilson. Subs not used: Gollini, Byrne.