Meanwhile, Boro had a happier week with a slender victory at home to fellow promoted side Hull City, as Gaston Ramirez scored against his former side to move the Teessiders up to 13th in the Premier League table.
The Saints will be without their top scorer Charlie Austin, after he suffered a shoulder injury in the Europa League clash with Hapoel Beer Sheva.
However, they were boosted in that game by the return from injury of playmaker Dusan Tadic as a substitute, while Jay Rodriguez and Sofiane Boufal should be fit after recovering from minor knocks.
Middlesbrough manager Aitor Karanka will make late calls on the fitness of Alvaro Negredo, Gaston Ramirez and Jordan Rhodes after they missed training on Friday, but all three are thought to be likely to play.
George Friend is expected to make his return to full training next week, with Fabio da Silva continuing to deputise at left-back in his absence.
This will be the first meeting between the two sides since Southampton's promotion from the Championship in 2011/12, when both sides won their respective home fixtures.
A Guly do Prado brace helped the Saints on their way to a 3-0 win at home, before Merouane Zemmama's free kick helped Boro overturn Billy Sharp's 47-second goal in a 2-1 win on Teesside.
Their last clash in the top flight came in March 2005, when Peter Crouch scored twice for Southampton as they came out on the right end of a 3-1 scoreline.
Stewart Downing played for Middlesbrough that day and could feature this time around as well if Ramirez is ruled out through injury.
Saints boss Puel is expecting a stern test from the travelling Teessiders on Sunday, stressing that his side must respond well after their European exit.
“I think they are a good team, and they try to play good football with good players like Negredo and Ramirez,” he told the club's official website.
"I saw them in their last games and it will be important to have a strong determination," he went on. "It's important for us to have a good reaction."
Meanwhile, Spaniard Karanka hopes that his side can strike the right balance against Southampton to disprove doubters who have accused Boro of playing overly defensive football.
“After good games against top teams, I had to hear that we are a defensive team,” he told the club's site.
“But then against Leicester City and Hull we showed we know how to play with the ball.
“Southampton is not a game like Hull where we are going to dominate the possession, but it is not like Manchester City or Arsenal where we have to defend a lot."