Al Ittihad are on a poor run of form, having won just two of their last nine games in all competitions.
The club's management had enough after Ittihad lost 2-0 to Iraq side Al Quwa Al Jawiya in the AFC Champions League on Monday.
Al Ittihad are currently sixth on the Saudi Pro League standings and trail leaders Al Hilal by eleven points.
Former Valencia, Wolverhampton Wanderers and Tottenham Hotspurs manager Espirito Santo was appointed Al Ittihad manager in July 2022 and led them to the Saudi Pro League title last season and the Saudi Super Cup.
This season, they have augmented their squad with the signings of Karim Benzema, N'golo Kante and Fabinho.
In a statement on X, Al-Ittihad said: "The club has announced the end of its contract with Portuguese coach Nuno Santo.
"This decision comes after a comprehensive technical evaluation of the past phase during which he was in charge of coaching the first football team."
