Duffy is the first Betfred Super League coach to lose his job this season.
His assistant-coach Kurt Haggerty will be in charge of the team for Sunday’s game at Wakefield Trinity.
Garreth Carvell, who played for clubs including Leeds Rhinos, Castleford Tigers and Featherstone, has left his role as head of rugby, also by mutual consent.
Leigh were chosen to replace Toronto Wolfpack in the top-flight this year, but have lost all eight of their league fixtures so far.
Centurions owner Derek Beaumont said: “I would like to thank John for his dedication, commitment and outstanding work ethic he has shown during his time with the club.
“In the end John wants the same as me, the best for the club, not himself and therefore it wasn’t a difficult conversation that we had.
“Something needed to change and we both recognised that.”
Duffy was appointed coach at Leigh in November, 2018, after leaving Rovers.
In a club statement, he said: “I am gutted that my time is up.
“I had a good chat with Derek and we agreed something needed to change.
“We have not got the results we needed and now it is time for someone else to step in and hopefully get the first win and then some more.”