The Terriers defeated promotion-chasing West Bromwich Albion 3-1 on Saturday (AEST) to all but secure safety in the second tier.
Cowley's brother and assistant Nicky will also depart the club, which is not seeking applications for a successor at the moment.
"I would like to place my thanks on record to Danny and Nicky for their hard work and dedication towards securing the club's place in the Championship for next season," chairman Phil Hodgkinson said.
"That was the clear priority when they were appointed in September and we are very grateful that has been achieved.
"We all wish Danny and Nicky all the best for the future and they leave with my best wishes in their future endeavours.
"However, we have made this decision in the belief that, in the long term, it is in the best interests of the club as we move forward.
"We have a different vision for the way we operate the club, and how our ambitions can be achieved."
Huddersfield is 18th in the table, three points above the drop zone with a game to go.
Prior to taking over at the club, Cowley had overseen Lincoln City's climb from the National League to League One.