The Hatters were one of the title favourites but are currently sitting in 10th spot, five points off the play-offs and 12 behind leaders Grimsby Town.
County have lost their last two, including a 2-1 home defeat to lowly Barnet last night.
Former Brighton under-23s manager Rusk was appointed in January and led Stockport to the play-offs last season after going 18 games unbeaten.
However, despite a big budget they have won just five of their 12 matches so far.
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Stockport said in a statement: “Following a difficult start to the season, the board have made the decision to part company with manager Simon Rusk.
“Simon will leave the club with immediate effect alongside assistant manager Mark McGhee, as the club restructures its coaching staff focused on future success and progression.
“We would like to thank Simon and Mark for their hard work, integrity, and dedication to the club during their tenure, including last season’s 18 game unbeaten run.
“In the interim, first team coach Dave Conlon will take the helm, with the support of the wider coaching staff.
“No further comment will be made until a new appointment has been made.”
Stockport become the latest club to depart with their manager after Barnet, Aldershot and Southend United opted to make a change in the dugout earlier in the campaign.
Chesterfield play the Hatters away on January 8 and at home on May 2.