The Saints last won a home game in the Premier League in March, while the visitors, second from bottom in the table, have one away win against the south coast outfit in 23 years.
Mauricio Pochettino's side has not won a league fixture at St Mary's since March, when goals from Jay Rodriguez and Rickie Lambert gave the Saints a 2-1 victory over Chelsea.
They have drawn both of their home top-flight matches so far this term - against Sunderland and West Ham - but go into this encounter with Ian Holloway's struggling Palace outfit after a morale-boosting 1-0 success at Liverpool last week.
Southampton followed the win at Anfield up with a 2-0 victory over Bristol City in the Capital One Cup third round on Tuesday, and one of the goalscorers from that game, Gaston Ramirez, is hoping his performance will help force his way back into Pochettino's Premier League plans.
"The level of competition is why I like being here," Ramirez said. "Me and my teammates know that only 11 players can start each game, so everybody is fighting hard to get into the team - myself included.
"I am very happy with how the Bristol City game went. These games are very important for me to get my confidence back. Now I have to keep working and waiting for my chance in the league."
Pochettino has a fully fit squad from which to choose after Daniel Fox (ankle) and Tadanari Lee (knock) returned against Bristol City. Southampton has lost just one of its five Premier League matches this campaign, and boast a defense that is tied for second best in conceding just two goals thus far.
By contrast, newly promoted Palace has found the going tough since winning promotion from the Championship, picking up just three points from a possible 15.
Holloway, who returns to the dugout for this game after serving a two-match touchline ban, has seen his side lose its last two games 2-0 to Manchester United and Swansea City, respectively.
Palace sits second from the bottom of the table, and goalkeeper Julian Speroni is under no illusions as to the size of the challenge the club faces this season.
"There are no easy games in the Premier League," Speroni said. "That's why we're here, to play against the best players in the world. It's going to be a tough game away from home but we're looking forward to the challenge."
Speroni suffered a head injury in the defeat to Swansea but expects to be fit for the trip to St Mary's, although Holloway has a lengthy absentee list with which to contend.
Jonathan Williams and Jack Hunt (both ankle), Yannick Bolasie (hamstring) and Glenn Murray (knee) are all long-term absentees, although captain Patrick McCarthy and Jonathan Parr could return for their first appearances of the season.