The Portuguese Football Federation (FPF) said it and Santos had “agreed to end” their journey since September 2014.
The FPF thanked Santos and his technical staff for their service.
During his more than eight-year spell, Santos, 68, led Portugal to the UEFA EURO 2016 title, the country’s first major trophy, and he secured the 2019 UEFA Nations League championship.
He had 67 victories in 109 matches to become the Portugal head coach with the most games and wins.
Portugal were eliminated in the World Cup quarterfinals last weekend after Morocco shocked the world with a 1-0 win in Qatar.
Source: Anadolu Agency