Wise, who made a cameo appearance in the 0-0 draw with Burnley, made his decision after meeting with chairman-elect Jeff Burnige and after discussing the Burnige's aims and ambitions for the club, decided to call it a day.
"I've had a meeting with the new chairman, he told me his direction and I didn't agree," said Wise this afternoon.
"I have had a long chat with the players and have decided that as of now, I am stepping down as manager of Millwall.
"I feel that it is important that the new chairman is allowed to get on with things; he has made it clear that he wants a fresh start and I think it is only fair that he is allowed to get on with it.
"I came in with Theo and I'm going with Theo. As far as (assistant boss) Ray Wilkins is concerned, he is meeting Jeff Burnige on Thursday, but he is totally separate to me."
Wise, who last season led The Lions to the FA Cup Final, signed a new one-year contract last December but his position was jepordised by Chairman Theo Paphitis' decision to quit his role and the appointment of his replacement Burnige, who made his feelings about Wise clear to those inside the club.
Wise took over as manager in October 2003, having joined as player the previous season, after Mark McGhee was sacked, leading The Lions into Europe.
Outgoing chairman Paphitis was quick to praise Wise for his time with Millwall.
"Dennis felt it was right to step down at this time," he said.
"It takes a very big bloke to put the club before himself, which is what Dennis is doing.
"He could have stayed, but Dennis feels it is right for Jeff and the club to move on.
"I would personally like to thank him for providing us with a couple of the most memorable years of our lives; years that are unlikely to ever be repeated."