Assistant coach Kelvin Davis will take the reins for Wednesday’s match against Tottenham Hotspur, as a report says Saints could be set to appoint former RB Leipzig manager Ralph Hasenhüttl to the post.
The club is also said to be considering former Watford boss Quique Sanchez Flores, and is looking at its former head of recruitment, Paul Mitchell, as a replacement for technical director Les Reed.
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Southampton lost a 2-0 lead in drawing Manchester United on Saturday, moving a point back of 17th place Huddersfield Town.
Hughes finishes his tenure at St. Mary’s with just three league wins in 22 matches, though he did rally the club to safety last season.
Saints visit Spurs on Wednesday before heading to Cardiff City in a big relegation six-pointer on Saturday. After that, it’s Arsenal and Huddersfield on the fixture list.
Southampton has one win this season, a Sept. 1 win at Crystal Palace.