The Reds will play in the Europa League next year after Newcastle and Manchester United got the points they required to seal Champions League football.
But Jurgen Klopp will hope he can still attract top players to Anfield in the summer despite not having elite European football.
Meanwhile, Southampton will want this campaign to be over as quickly as possible.
The Saints' 11-year run in the top-flight is at its end and they have lost eight of their last nine games in the Premier League.
This is also set to be Ruben Selles' final match in charge, with talkSPORT understanding Russell Martin will be confirmed as the new Saints boss soon.
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Southampton vs Liverpool: talkSPORT coverage
This final Premier League clash of the season is set to take place on Sunday, May 28.
Kick-off at St Mary's is scheduled for 4:30pm.
talkSPORT will have live coverage from the south coast, with Ben Jacobs providing commentary via the talkSPORT App.
talkSPORT.com will also have a live blog taking you through all of the final day's games.
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To tune in to talkSPORT or talkSPORT 2 through the website, click HERE for the live stream.
You can also listen via the talkSPORT app, on DAB digital radio, through your smart speaker and on 1089 or 1053 AM.
Southampton vs Liverpool: Team news
The Saints are without Romain Perraud after the Frenchman suffered an ankle injury.
Armel Bella-Kotchap is out with a hamstring problem. Mohammed Salisu and Juan Larios also won't play any part.
But Che Adams could return from a calf issue to feature at St Mary's.
Meanwhile, Klopp is expected to ring the changes but will be without Thiago Alcantara, Calvin Ramsay, Stefan Bajcetic and Naby Keita.
Ibrahima Konate is doubtful due to illness and Andrew Robertson has a groin problem.
But Darwin Nunez has fully recovered from his foot injury and will be involved.
Southampton vs Liverpool: What has been said?
Speaking about having nothing to play for ahead of this match, Klopp said: "I am not used to final matchdays where everything is sorted.
"Usually, everything is at stake, but we play the game to win it with desire and we have to see.
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"I won't take any risks with players but we have a big group, and in training, we looked good."
Southampton vs Liverpool: Match facts
Southampton have lost 10 of their last 11 Premier League games against Liverpool, with the exception being a 1-0 home win in January 2021.
Liverpool haven't conceded more than once in any of their last 13 Premier League games against Southampton, shipping just five goals in total since a 3-2 loss at St Mary's in March 2016.
Southampton have lost their final league game in each of the last two seasons, going down 4-1 at Leicester last season and 3-0 at West Ham in 2020-21. They've not lost their last game in three consecutive campaigns since doing seven in a row between 1932-33 and 1938-39.
Liverpool have won their final league game in each of the last six seasons, since a 1-1 draw at West Brom in 2015-16. Their last such defeat was a 6-1 hammering at Stoke in 2014-15.
The team finishing bottom of the table (Southampton this season) has won their final Premier League game in just one of the last 20 campaigns, with Sheffield United beating Burnley 1-0 in 2020-21.
Southampton are winless in their last 12 Premier League games (D3 L9). Only twice in their league history have they had a longer run without a win, going 20 games between August-December 1969, and 17 games between November 1988 and March 1989.
Liverpool have won their last three Premier League away games, as many as they had in their first 15 on the road this season (D4 L8). They've scored 11 goals in these three victories, as many as in their previous 13 away league games.
If he plays for Liverpool in this match, it will be James Milner's 16th appearance on the closing day of the Premier League season, the joint-most in the competition's history (Ryan Giggs, Paul Scholes, Jamie Carragher and Gareth Barry also 16).
Of everyone to score at least 20 combined Premier League goals across the last three seasons, Southampton's James Ward-Prowse has scored the lowest percentage of them in home games, with just six of his 26 goals in that time coming at St Mary's Stadium (23%).
Liverpool's Mohamed Salah has been involved in 17 goals in 14 Premier League games since the start of March (11 goals, 6 assists), more than any other player in the competition in that time.