The News can reveal he has agreed to replace Ian Holloway who quit the Tangerines for Crystal Palace.
Appleton became Pompey boss in November 2011 and leaves after just under a year at Fratton Park.
First team coach Ashley Westwood has also gone to Blackpool while Guy Whittingham will take charge of the Blues for the match at Bury.
A Pompey statement read ‘Portsmouth Football Club can confirm that we reluctantly gave Michael Appleton permission to speak to Blackpool and that he has since agreed to become their new manager.
‘Michael has done an incredible job in very difficult circumstances at Pompey and we have done what we can to keep him at Fratton Park.
‘However, he is an ambitious manager with a growing reputation and has deservedly attracted interest from other clubs.
‘First team coach Ashley Westwood has also left Pompey to link up with Appleton at Blackpool.
‘We thank them both for the work they have done here and wish them well for the future.
‘Guy Whittingham will take charge of the side for Saturday’s League One match at Bury.’