The move comes after the Vikings' 21-17 loss to the Seattle Seahawks on Monday night, the team's third defeat in its past four games.
Minnesota, who were one the pre-season favourites to win the Super Bowl, finished the game with 276 yards of total offense, managing just 61 in the first half.
It was the fourth time in the past five games that the Vikings have finished with less than 300 yards total offense.
Quarterbacks coach Kevin Stefanski has been elevated to interim offensive coordinator and will take over play-calling duties for the Vikings.
The Vikings entered November with a top-10 offense but have dropped to 17th after Monday night's loss.
Head coach Mike Zimmer had been critical of DeFilippo's play-calling recently, saying that the Vikings have not been committed enough to the running game.
Running back Dalvin Cook rushed 13 times for 55 yards against the Seahawks, just the second time this season Cook has had more than 10 carries.
The Vikings (6-6-1) are vying for a wild-card spot and play host to the Miami Dolphins on Sunday.
The Vikings hired DeFilippo in February to replace Pat Shurmur, who left to become the head coach of the New York Giants.
DeFilippo spent two seasons as quarterbacks coach with the Philadelphia Eagles and was previously offensive coordinator of the Cleveland Browns.
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