The Saints are hoping to claim a place in the Europa League while the hosts will wave goodbye to Frank Lampard as he leaves the Premier League and moves to New York CitySouthampton boss Ronald Koeman does not believe Manchester City will do his side any favours in their chase for European football on Sunday.
The teams meet at the Etihad Stadium in the final round of Premier League fixtures and, along with the battle between Hull City and Newcastle United to avoid relegation, the fight for a place in the Europa League is one of the top-flight storylines yet to reach its denouement.
City are already assured of second place and their spot in the Champions League group stage for next season, but seventh-placed Southampton will have to muscle their way past Tottenham or Liverpool - one and two points ahead respectively - to ensure their ticket to the continent via a top-six finish.
"They are professional, they're playing at home and they'd like to finish their season in a good way," Koeman said of Sunday's hosts.
"It's a tough one. They have a strong team with good individual players, but we believe in ourselves that we can get a good result.
"It's still a fantastic season. Of course it makes it more special if we reach Europe in league football."
Tottenham and Liverpool travel to Everton and Stoke City respectively, and Koeman believes Southampton will have a chance to force their way into the top six.
"If we win on Sunday, I think that means that we will be sixth or fifth in the league because I think not all the other teams will win difficult away games," he added. "I don't think they will both win away, but ours is maybe the most difficult.
"But we've beaten Manchester United, we had a draw against Chelsea - why can't we win against Manchester City?"
If Arsenal triumph over Aston Villa in the FA Cup final, seventh would be enough for a place in Europe.
The fixture will also see Frank Lampard wave goodbye to the Premier League ahead of his move to New York City, who loaned the legendary midfielder to the Etihad Stadium outfit for the season following his Chelsea exit at the end of last term.
Asked for his assessment of Lampard's contribution, manager Manuel Pellegrini said: "Very pleased. I think Frank is one of the most important players in Premier League history.
"His career is brilliant, he's a great professional and I think it's been a proud moment for this team to have him here playing for the season."
Southampton are without Morgan Schneiderlin (knee) and Dusan Tadic (groin), while Jay Rodriguez (knee) is set to travel with the squad but will not be considered for selection.
Samir Nasri (groin) is City's only absentee through injury.
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