The Saints were enduring a torrid spell under the Argentine, with just one win coming in their last 17 Premier League games. Hovering just one spot above the relegation zone Southampton are in danger of losing the top-flight status they acquired six seasons ago.
Hughes has taken charge of almost 450 Premier League matches for Blackburn, Manchester City, Fulham, QPR and Stoke.
"As far as the situation we are in at the moment, I think it makes sense to go with someone who has Premier League experience - who doesn't have to get to know a new set of players".
"The club will look to appoint a new management team as soon as possible, with the search for a replacement already underway".
Assistant manager Carlos Compagnucci and assistant first-team coach Xavier Tamarit have also parted company with the south coast club.
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South African seventh seed Kevin Anderson also prevailed in his second round match, 7-5 6-4 over Russian Evgeny Donskoy . The win sets up a third round showdown with Spaniard David Ferrer who defeated Tennys Sandgren of the USA 6-2, 7-6 (7/3).
He eventually left the club in the summer, supposedly to retire, but ended his self imposed retirement to help Everton, who were flirting with the relegation zone, back in November of this season.
So they hired Pellegrino, and nine months on they must be regretting their decision.
The former England boss is THE anti relegation specialist, becoming the firefighter to extinguish all relegation threatened Premier League blazes, having never been previously relegated in his career.
The ex-Watford boss was immediately made the stand-out favourite to take over at St.Mary's stadium after Pellegrino was relieved of his managerial duties on Monday, but reports have since suggested otherwise.