The former Fratton Park striker leaves with his side struggling towards the lower reaches of League Two after a summer of great optimism engendered by a supporters' takeover of the club after years of financial problems.
A statement on the club website said: "Portsmouth Community Football Club regret to announce that Guy Whittingham has left his post as manager after his contract was terminated.
"The club wishes to place on record its sincere gratitude to Guy for his service to the club during difficult times."
Northampton travel to Fratton Park on 29 December for what will be (barring a plum FA Cup away tie) the biggest attendance they play in front of this season.
Portsmouth are averaging 15,735 at home this season, by far and away the largest crowds in the division.