He is the club’s third manager of the season already.
The LaLiga side started the season with José Luis Mendilibar in charge before appointing Diego Alonso.
Flores has not managed since he managed Getafe in LaLiga.
He resigned in February with the club in the relegation, citing personal reasons.
Flores is known in England for his two stints as Watford coach.
He first managed the club between 2015 and 2016, guiding the team to the semi-finals of the FA Cup and achieving a midtable finish.
Despite this, he was dismissed in May 2016.
He returned to the club in September 2019 but his ill-fated spell lasted only until November after achieving just a single victory.
One fan on Twitter said: “Sevilla three coaches a season” alongside a laughing emoji.
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That led one to reply: “He should be used to it!” after Flores’ spell in charge of trigger happy Watford.
Another fan wrote: “The Sevilla hot seat is getting plenty of action! Can’t wait to see what Quique brings to the table. Exciting times ahead for the team!”
While another wrote: “Getting sacked in February.”
Sevilla are having a disastrous season so far this season.
The club are completely out of Europe and skirting around the edges of the relegation zone.