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Setien's side lost three of their opening four games and stand 15th in the table.
"Villarreal CF announce that first-team coach Quique Setien is leaving the club," read a statement released by the club.
"The club would like to highlight his great professionalism and commitment and thank him and his coaching team for taking charge in a complicated situation last season."
Setien arrived at the end of October 2022 after Unai Emery quit suddenly to take over at Aston Villa.
He responded by promoting a number of youngsters from the academy and qualifying for the Europa League after finishing fifth in La Liga.
This season, however, has been more complicated as they slipped to home defeats against Barcelona and Real Betis as well as losing at Cadiz.
The 64-year-old had an even shorter spell in charge of Barcelona, sacked in August 2020 after just seven months in the job.
Director of football Miguel Angel Tena takes over as caretaker boss until Villarreal find a replacement.