The Frenchman, whom the defender describes as his side's "best player this season", has a hamstring problem, though manager Alan Pardew is optimistic that it will only keep his star attacking midfielder out for two weeks.
"He's a really big player for us," Santon told the Northern Echo. "I think we will miss him.
"He's an amazing player and we need him on the pitch. We will have to try a different type of player. He's been the best player for us this season and being without him will be difficult for us on Sunday. But we have to win, 100 per cent, because we need this win."
Injuries and suspensions have dogged Newcastle this year, with Yohan Cabaye and Fabricio Coloccini both also to miss the Saints clash, and Santon acknowledges the frustration of the season.
|THE EVER-PRESENT'S INFLUENCE|
|13/1||Davide Santon is 13/1 with PaddyPower to score anytime in Southampton v Newcastle|
"This is the toughest time the club has been through since I've been here," said the Italian. "Last year was a really great year, finishing in fifth position. This year has been a little bit more difficult.
"We've had a lot of players injured and suspended but we can't just think it's difficult, we've got to be positive and just think about getting a win at Southampton. We've all got to give a little more and it's important for us to work hard. We won't have Hatem so we just have to keep playing and try to find a solution to win the game."
The disruption to their squad means that Santon is the only Magpies player to have featured in every Premier League game so far this campaign and the defender noted that the unsettled nature of the team may have contributed to their run of no wins in five games.
"It's difficult because if you're playing with the same players, it's easier," the former Inter man added. "But when you change the players every game because one's injured or one's suspended, it's difficult to keep the same performances. It's just tough."