The big-spending Tractor Boys made the decision after the Portman Road side’s goalless draw with Barrow in the second round of the FA Cup.
Cook’s departure comes just nine months after his appointment to the Ipswich hot seat and following a less than impressive start to the 2021-22 campaign.
Despite splashing the cash on 19 players during the summer, the Suffolk side currently sit 11th in the table with 27 points from their 20 games played.
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They’ve already suffered seven defeats in the third tier this term and are 11 points behind league leaders Rotherham.
The Tractor Boys also sit five points and two places below Pompey in the table – despite Cook enjoying a 4-0 victory on his return to Fratton Park in October.
However, since then Ipswich have won just three times in the league, while they crashed out of the Papa John’s Trophy during the week following a penalty shootout defeat at the hands of Arsenal’s under-21s.
Town CEO, Mark Ashton, said in the tonight’s statement: ‘Firstly, we would like to thank Paul and his team for their efforts in what has been a difficult transition period for everyone.
‘I know how much Paul wanted to succeed at this club. However, following discussions with the board, we have decided a change is needed for our long-term interests.
‘At this moment, there is no one lined up to replace Paul.
‘There will be an extensive search to find the best replacement for the club.’
Cook guided Pompey to the 2016-17 League Two title, before leaving to manage Wigan soon afterwards.