The Posh are bottom of the League One table and went down 2-1 at home to Blackpool on Saturday afternoon.
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"I have made the decision to terminate Darren Ferguson's contract after today's game," MacAnthony said in a statement. "The decision wasn't taken lightly but it's a decision I feel is the correct one for the football club.
"The gaffer is for me the greatest manager in the club's history who I will always consider to be part of my family and the club's family.
"There are too many wonderful moments to mention here but those many historical celebrated moments I will cherish and remember forever."
The latest spell was the fourth time Ferguson has been charge of Peterborough.