Wolves, meanwhile, still have an outside chance of finishing in the top half for a third successive season.
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However, Brighton, who have all but avoided relegation with four games to spare, make the trip to Molineux sitting just five points adrift of their hosts
Wolves, meanwhile, will be aiming to extend their winning run to three matches.
The Blades are 18 points adrift and it will be mathematically impossible for them to escape the drop should they lose at Molineux and Newcastle United beat West Ham United.
The Premier League club will then be in position to introduce safe standing should any change in UK law occur.
The clubs are meeting for the second time in three days after the Saints prevailed in the FA Cup fifth round on Thursday night.
Brendan Rodgers’ side would have gone level with Manchester United in second with victory but were forced to settle for a 0-0 draw at Molineux.
Meanwhile, the home side head into the contest at Molineux on the back of a much-needed 2-1 win against Arsenal, a result which has moved the club 12 points clear of the relegation zone.
“It’s been a long time coming,” he said in his post-match interview. “We work hard all the time and it’s not come off for us, but today it worked so I’m grateful.
Wolves had knocked Palace out of the cup by the same scoreline when they met earlier this month.
Palace will enter today’s contest off the back of a 3-2 home defeat to West Ham United on Tuesday, while Wolves held Thomas Tuchel’s Chelsea to a goalless draw at Stamford Bridge on Wednesday.
The German, who replaced Frank Lampard on Tuesday, watched his side create 14 shots on goal but saw them unable to find the breakthrough
While the home side have gone five matches without recording maximum points, the Baggies last recorded success on November 28 when they edged out bottom-placed Sheffield United.
Alex Iwobi finished off a lovely team move to put the visitors ahead after six minutes on Tuesday night.
Their hosts, meanwhile, have slumped to seven games without a win and are looking nervously at the clubs below them in the Premier League relegation dogfight.
Spurs have lost their last two in the league to Liverpool and Leicester City, which has seen them drop down into eighth position in the table, while Wolves currently occupy 11th position.
After a drab first 45 minutes where only a Kurt Zouma header that rocketed back off the crossbar threatened either goal, Olivier Giroud put Chelsea ahead when his effort squeezed through Rui Patricio and was awarded by goal-line technology.
The substitute struck from the spot in injury time after Nelson Semedo brought down John McGinn.
The Egyptian took advantage of an error from ex-Reds defender Conor Coady to steal in and fire home the opener on 24 minutes.
Jurgen Klopp’s side head into the weekend with only goal difference keeping them off the top of the table, but Wolves could move to within just one point of their opponents if they end the Reds’ long unbeaten run at home.