Mauricio Pochettino's men have gone seven games without a loss in all competitions since losing to Chelsea on New Year's Day.
Their previous run included a 4-1 demolition of Hull at St Mary's Stadium, which saw Morgan Schneiderlin, Adam Lallana, Rickie Lambert and Steven Davis all get on the scoresheet.
A win at the KC Stadium could see Pochettino's side leapfrog Newcastle United into eighth in the Premier League, and the omens are good - they have defeated Hull in their last three meetings.
Steve Bruce's men have won five times at home this season, and only conceded nine goals in their 12 games at the KC.
Saturday's 2-0 win at Sunderland was Hull's first league win in 2014. Before then, Bruce's men had lost four and drawn one of their five games, though that run involved two morale-boosting FA Cup wins.
They have scored only three goals in the league this year, but they all came from their January signings. Shane Long has hit the ground running, with two goals already and Nikica Jelavic opened his account for the club at Sunderland.
Hull are two places behind their opponents in the league, but nine points adrift. Despite this, Bruce could steer his side into the top half of the league with a win.
The two sides have met four times at the KC Stadium. The visitors have tasted victory twice, and there has been one draw, while Hull's solitary win came in 2008 - an emphatic 5-0 victory.
Southampton have no new injury problems, but the game will probably come too soon for Dejan Lovren and Gaston Ramirez, who are both back in light training.
For Hull, Sone Aluko made a short cameo at the Stadium of Light after Achilles trouble but, given the form of Jelavic and Long, may have to again settle for a place on the bench.
James Chester remains absent with a hamstring problem, while Allan McGregor serves the final game of his three-match ban. Steve Harper will once again deputise.
