Saints bounced back from defeat against Manchester United by steamrollering MK Dons on their own patch.
Ronald Koeman fielded a strong side, featuring many first team players, while Jay Rodriguez entrusted with the responsibility of leading the line in Graziano Pellè's absence.
The first goal of the game came after just five minutes, with Rodriguez motoring away from three white shirts before curling an effort past David Martin in the Dons' goal.
Sadio Mané then doubled the advantage, running the MK Dons backline ragged before serving up a cheeky chip to defeat Martin.
After 25 minutes, Saints found themselves 3-0 up, as Mané struck again. This time the Senegalese forward combined with Shane Long, before cutting back onto his left foot and firing an effort into the back of the net.
Three became four within three minutes of the restart, with Long going down under pressure, enabling Rodriguez to convert from the penalty spot.
Ryan Bertrand then returned to senior action, replacing Matt Targett after 55 minutes. Gastón Ramírez then took to the field in place of Mané, making his first competitive appearance for Saints in over 12 months.
Ramírez was involved in Southampton's fifth in the 68th minute, lofting an angled pass over the MK Dons defence for Juanmi, who then squared the ball, with Long sending the ball over the goal-line as the scoreline grew.
The scoring was completed 15 minutes from time, when Long raced on to an exquisite through ball from Steven Davis, before blasting past Martin to make it 6-0.
Maya Yoshida replaced Virgil van Dijk for Koeman's final change, as Saints coasted to victory.
Southampton will now host Aston Villa at St. Mary's in the last 16 of the Capital One Cup.
Saints: Stekelenburg; Cédric, Fonte, Van Dijk (Yoshida - 78'), Targett (Bertrand - 55'); S. Davis, Romeu; Mané (Ramírez - 66'), Juanmi, Long; Rodriguez.
Unused Subs: K. Davis, Wanyama, Ward-Prowse, Tadić.