Former fan-favourite Whittingham took over the reins at Fratton Park in November 2012 but only managed 11 wins in 51 attempts during his time in charge.
Pompey currently sit 18th in Sky Bet League Two and host Phil Brown's in-form Southend side on Tuesday evening looking to end a run of four successive defeats.
A statement on the club's website said: "Portsmouth Community Football Club regret to announce that, following a meeting with the chairman, CEO and finance director, Guy Whittingham has today 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.
"Andy Awford has been put in caretaker charge, assisted by Alan McLoughlin and David Connolly.
"We have an important game against Southend United tomorrow night which we are fully focused on and there will be no further statement until after this fixture."