The home side are playing their final Premier League game at the Riverside before they drop down to the Championship.
The away side know a win could see them move up to the top of the mini-league forming in the middle of the Premier League. Just a mere seven points separate eighth and 16th place, and with the Saints currently sitting in 10th position, they will be determined to finish as high as possible.
Boro saw their slim Premier League survival hopes crushed on Monday, as Champions Chelsea swept them aside at Stamford Bridge.
The Teesside outfit have struggled this campaign, mustering only 26 goals and five wins thus far.
Southampton have also had a frustrating season so far. Claude Puel has failed to build on the foundations left by Mauricio Pochettino and Ronald Koeman, with his style being criticised by Saints fans for not being attractive enough.
The South Coast outfit have failed to win since the start of April, adding to fans' frustrations.
As mentioned, both sides have not faired well recently. Boro have only won one game in 2017, against rivals and bottom club Sunderland. Seven of their last 11 games have ended in defeat.
For Southampton, their winless run stretches to four games. However, their last four games have been against sides in the top six. The Saints have only won one of their last four matches on the road.
On a positive note, Middlesbrough have scored four goals in their last five games at the Riverside Stadium.
Victor Valdes, Daniel Ayala and Gaston Ramirez are all set to miss out Steve Agnew's side. Adlene Guedioura is also doubtful.
Stewart Downing, Adama Traore and Alvaro Negredo are the likely attacking trio.
Puel has no fresh injury worries and will be helped by the potential return of striker Charlie Austin.
The Frenchman may stick with the same side that were beaten by Arsenal on Wednesday, however Jordy Clasie, Pierre Emile-Hobjberg and Matt Targett may be brought in if the manager opts to rest some first team players.