The bookies have the former Watford boss at just 8/11 to be the next Saints boss after Hughes was sacked on Monday morning.
Behind Sanchez Flores in the market is former RB Leipzig boss Ralph Hasenhuttl.
Prior to Southampton's 2-2 draw against Southampton, Paulo Sousa was leading the market but he is now third favourite at a huge 10/1.
Betfair Spokesperson Katie Baylis said: “With confirmation Hughes has been given the boot from Southampton, attention turns to who will take over.
"We’ve seen a flood of bets on Sanchez Flores over the weekend and his odds have gone from 14/1 before the weekend, to 2/1 yesterday with the former Watford manager now backed into odds-on favourite at 8/11 as of this morning.
"Hasenhuttl is the 5/2 second favourite with Sousa at 10/1, but at the moment it looks like Flores could be heading back to England.”
Betfair: Next Southampton manager
Quique Sanchez Flores 8/11
Ralph Hasenhuttl 5/2
Paulo Sousa 10/1
Gary Monk 14/1
David Moyes 16/1
Peter Bosz 16/1
Leonardo Jardim 20/1
Sam Allardyce 20/1
Brendan Rodgers 33/1
Steve Bruce 33/1
Louis van Gaal 40/1
Gordon Strachan 50/1
Frank Lampard 60/1
Marians Pahars 66/1
Mark Warburton 75/1
Alan Curbishley 90/1
Gary Megson 100/1
Matt Le Tissier 100/1
Hughes is the second Premier League manager of the season to be sacked, after Fulham axed Slavisa Jokanovic.
Southampton decided to call time on the 55-year-old's time as boss after a ten-game winless streak in the English top flight.
First Team Assistant Coach Kelvin Davis will lead the team for Wednesday’s Premier League game against Tottenham Hotspur at Wembley.
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