Tonda Eckert made five changes to the team that drew at home to Millwall on New Year's Day.
Joshua Quarshie came back into the starting lineup to replace Jack Stephens, which also saw Adam Armstrong, Finn Azaz, Caspar Jander, and Tom Fellows selected.
Southampton started well before Middlesbrough gained the upper hand in the first half. Boro's press made it difficult for the Saints' defence to keep the ball or progress it up the pitch.
Despite that, Armstrong, Azaz, Flynn Downes, and Tom Fellows had half-chances which they snatched at as Southampton got themselves on top as half-time approached.
On the stroke of half-time, Tom Fellows blazed a golden chance over the bar from 10 yards after being put through on goal by Finn Azaz.
Middlesbrough opened the scoring when former Saint, Matt Targett, slid Morgan Whittaker in after a cleverly worked free kick. Whittaker kept his head and slid the ball between Gavin Bazunu's legs and into the net.
Ryan Manning was caught out by a long pass by Luke Ayling, which allowed Sam Silvera to ghost in behind him and coolly slot the ball past Bazunu for Boro's second goal.
Manning was at fault again when he failed to clear properly and gifted the ball to Boro in his own area. When the ball fell to Morgan Whittaker, he made no mistake, sending Bazunu the wrong way before finding the corner of the net.
Gavin Bazunu failed to hold on to Hayden Hackney's tame effort after another well-worked corner gave him a chance to shoot from a tight angle. The ball fell to the feet of Alan Browne who couldn't miss from close range.
Full Time: Middlesbrough 4-0 Southampton
Goalkeeper and Defenders
Gavin Bazunu (GK) - 4/10 - Easily beaten from close range for Boro's opener after having little to do in the first period. Too easily beaten by Sam Silvera for Boro's second but could do nothing about the third. Failed to hold on to Hayden Hackney's tame shot, allowing Alan Browne to tap in Boro's fourth goal.
Taylor Harwood-Bellis (RCB) - 6/10 - Played some good balls out of defence to Finn Azaz in the first half, which got Saints forward quickly at times.
Nathan Wood (CB) - 6/10 - Much better than on New Year's Day when he started the game on the right before being moved to the left side of the back three.
Joshua Quarshie (LCB) - 6/10 - Started the game well when his pace got the Saints out of trouble early in the first half as Middlesbrough counter-attacked.
Midfielders
Tom Fellows (RWB) - 6/10 - Did all of his best work in the opposition half and almost put the Saints ahead on the stroke of half-time when he blazed over the bar from 10 yards out. Anonymous in the second half.
Ryan Manning (LWB) - 4/10 - Caught out of position a couple of times in the first half and resorted to trying to buy free kicks and general skullduggery to cover up the cracks. Bailed out by Jander and Quarshie when he struggled to recover in defensive transitions. Not so lucky when he allowed Sam Silvera to ghost in behind him for Boro's second. Manning was at fault for the third goal, too, when he failed to clear properly.
Flynn Downes (CM) - 6/10 - Probably should have put Saints ahead when he ran on to a Finn Azaz cut back. Despite having plenty of time to pick his spot, Downes could only hit his shot tamely against a Boro defender.
Caspar Jander (CM) - 6/10 - Covered a lot of ground in the first period and looked refreshed after being rested for most of the match against Millwall. Tired quickly after half-time, though, and was replaced on the hour by Cameron Bragg.
Forwards
Léo Scienza (AML) - 5/10 - Slow to get into the game again, but looked more threatening before fading later in the game.
Finn Azaz (AMR) - 6/10 - Had an excellent first half, creating clear-cut chances for Fellows and Downes. An abysmal second period in which he gave the ball away too easily and failed to create anything.
Adam Armstrong (CF) - 5/10 - Full of running in the first half and saw a volley flash narrowly wide after 13 minutes when he really should have hit the target. Went missing in the second half and was replaced by Cameron Archer after 74 minutes.
Substitutes:
Cameron Bragg - 5/10
Cameron Archer - 5/10
Welington - 6/10
Elias Jelert - 6/10
Ross Stewart - N/A