Cruyff, 44, son of the late Dutch footballing legend Johan, joined the club in 2012 after a successful first management spell at Cypriot club AEK Larnaca and served first as sports director then as coach.
As well as back-to-back titles in 2013, 2014 and 2015, Maccabi also won the Israel State Cup in 2015 and the Toto Cup in 2014.
In a statement on its website, the club gave no reason for Cruyff's departure and no indication of his future plans.
Cruyff began his playing career with Barcelona making his top-flight debut in 1994, before signing for Manchester United in 1996.
His spell at the English giants was plagued by injury problems and in 2000 he moved to Spanish club Alaves on a free transfer.
The following year the club reached the UEFA Cup final against Liverpool and in the 89th minute Cruyff levelled the score at 4-4 to send the game into extra time. But an own goal in the second half gave the title to Liverpool.
He spent brief spells with other clubs before announcing his retirement in 2010 and moving into management.