Twente were beaten by Heerenveen on Saturday and, despite receiving the backing of club chairman Joop Munsterman, the 51-year-old opted to head for the exit.
McClaren led the side to the Eredivisie title during his first reign at the club in 2010, but has failed to repeat the same level of success since returning to the the Tukkers in 2012.
The fans began to turn on the ex-Middlesbrough boss, with the club six points behind league leaders PSV Eindhoven in the table and without a win in 2013.
Twente also crashed out of the Europa League in the group stage after finishing bottom of Group L with just four points.
McLaren, who also endured short managerial stints at Wolfsburg and Nottingham Forest, was sacked as the Three Lions coach in 2007 after failing to qualify for Euro 2008.