Pools’ 2-0 defeat at their fellow strugglers left them just two places and three points off the bottom four in the National League.
Former The New Saints boss Harrison joined Hartlepool in the summer following their relegation from League Two but it has been another difficult season for the club.
Matthew Bates and Paul Jenkins will take charge of training and prepare the Pools side for Saturday’s home fixture against Ebbsfleet United.
A club statement read: “Hartlepool United have terminated the contract of manager Craig Harrison, who has left the club with immediate effect.
“We appreciate that, in recent months, Craig has had to work in extremely difficult circumstances due to the uncertainty over the club’s future.
“Hartlepool United would like to place on record its thanks to Craig for his hard work and professionalism during this period, and wishes him and his family well for the future.”
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