The Saints remain rooted to the foot of the table and they are on the brink of relegation as they sit eight points adrift of safety with just three games remaining.
Ruben Selles's side will be relegated to the Championship if they fail to claim maximum points against Fulham, who won the reverse fixture 2-1 at Craven Cottage in December.
Southampton enter Saturday's contest having endured a torrid 10-game winless run in the Premier League, losing seven games and conceding 23 goals in the process.
The Saints' latest setback came at the City Ground where they ended up on the wrong side of a 4-3 scoreline against relegation rivals Nottingham Forest on Monday night.
Southampton have now lost 23 of their 35 Premier League games this season, and another defeat on Saturday will see the South Coast club record 24 losses in a single league campaign for the first time in their 138-year history.
Along with this season, the Saints have lost 23 league games in a single season on two previous occasions back in 1971-72 and 1993-94.
The prospect of Southampton claiming a positive result on Saturday is slim as they boast the worst home record in the Premier League this season, winning two, drawing four and losing 11 of their 17 matches at St Mary's.
However, the Saints boast an impressive home record against Fulham as they have only lost one of their 31 league encounters with Fulham in front of their own fans and are also unbeaten in each of their last 21 home meetings with the Cottagers since a 2-1 defeat back in October 1935.
Selles has insisted that his Southampton side will fight until the very end to beat Fulham, but has admitted that he is struggling to motivate his players for the season-defining fixture.
"It's our job and our privilege to fight until the very last minute and that's why we are going to do it," Selles said at a press conference on Friday.
"We know it's very close there but we still have our chances. It's not mathematically there yet so we are going to go for it, we are going to be there until the very last second.
"It's getting harder [to motivate my players] of course because the situation is not helping and it has been a tough week for us.
"We put all we have in against Nottingham Forest and we didn't get the result that we want, and always when you get hit like that it's difficult to get the day after to walk and then to be super motivated.
"I think we are in a good place and I think we are getting to a place that we can go tomorrow, compete and try to win the game."
Southampton will be without Mohammed Salisu, Juan Larios, Romain Perraud and Armel Bella-Kotchap due to injury, while top scorer Che Adams is doubtful and will be assessed ahead of kickoff.