Slot picked up his third yellow card during Liverpool's 2-2 draw with Fulham in the Premier League on Saturday.
That is the threshold for an automatic ban for top-flight managers, with players permitted two more cautions before being punished.
Crystal Palace defender Daniel Munoz was among those who have hit that mark, but unlike Slot, he is available for Carabao Cup duty.
Why is Slot banned against Southampton?
The 46-year-old will serve his one-match touchline ban in the Carabao Cup due to a unique ruling outlining manager suspensions.
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As per FA guidelines, player red cards carry across all domestic competitions and are instantly served in the next available match.
Bans handed out by an accumulation of yellow cards are restricted to the Premier League, which is why Munoz can play the Carabao Cup match against Arsenal but not the top-fight encounter a few days later.
However, this does not apply to managers, where suspensions do carry across different FA competitions regardless of the type of ban.
A similar scenario has already taken place this season, ironically with Liverpool's opponents Southampton and their now-ex-manager Russell Martin.
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The recently sacked Saints boss missed their win over Stoke City in the round of 16 after picking up his third Premier League booking.
Andy Robertson will also miss Liverpool's trip to St Mary's after being sent off against Fulham but can return this weekend.
In Slot's absence, his assistant Sipke Hulshoff will likely be the man to take charge, with the pair communicating via phone to the dugout.
The former was cautioned in the 57th minute of the 2-2 draw with Fulham after reacting to Curtis Jones' being booked for a mistimed challenge on Alex Iwobi.
"There were a few moments when I could have been given a yellow card," said Slot, who also picked up yellows against Chelsea and Arsenal.
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"It's an emotional game and we were a man down, it's frustrating. It's good to see our performance after so many setbacks.
"It's difficult to judge for me because I only see it in real-time like the referee.
"We have to accept what VAR sees. You know how important these decisions can be. We ended up with a draw and I don't think we can blame the referee for that."
Southampton vs Liverpool: How to follow
This Carabao Cup quarter-final clash is set to take place on Tuesday, December 10.
Kick-off at St Mary's is scheduled for 8pm.
talkSPORT 2 will have live coverage from the south coast, with commentary from Jim Proudfoot and former Chelsea defender Scott Minto.
talkSPORT.com will also have updates in our dedicated live blog.
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