It's a marked contrast from last season when the team were Runners-up in the Premier League. This season, Motherwell have won only two of their 12 Premiership matches and are second bottom of the table.
Assistant boss Kenny Black has been named caretaker manager.
Motherwell director Derek Weir said ex-Rangers and Everton midfielder McCall's tenure was "one of the most successful in our 128-year history".
Former Bradford City manager McCall, 50, who joined Well in 2010, led them to the Scottish Cup final in 2011 and finished in the Premiership top three in the last three seasons.
McCall also guided the Fir Park side into the Champions League qualifiers in 2012, where they lost to Panathinaikos.
However, they have struggled in the league this season and were knocked out of the League Cup when they lost to Lanarkshire rivals Hamilton on penalties.
Weir added: "We have been acutely aware of results this season, but everyone at Fir Park was confident in Stuart, and the team's, ability to turn things around.
"However, following a long conversation this afternoon, Stuart felt it better for all concerned if he stepped down with immediate effect and we respect that."
McCall is the second Premiership manager to depart this season after Ross County sacked Derek Adams in August.