The former Pompey skipper and his backroom staff have departed Roots Hall by mutual consent after less than a year in charge.
Campbell succeeded Kevin Bond as Shrimpers boss in October 2019.
However, the Blues' 2008 FA Cup-winning captain was unable to turn around Southend's fortunes following their woeful start to the campaign.
The ex-England centre-back managed just three victories as the Essex side were relegated to League Two after the campaign was curtailed amid the coronavirus crisis.
Along Campbell, former Fratton favourite Hermann Hreidarsson leaves his role as assistant, while Andy Cole departs having served as striker coach.
A spokesman for Southend said: ‘We are grateful to Sol Campbell for his contribution whilst manager. Sol arrived at a time when the team were struggling and began to make a difference just as Covid-19 interrupted the season.
‘Sol’s use of the club’s young talent was a breath of fresh air who responded well to his stewardship.
‘The club wishes to thank Sol and wish him, together with his management team, well for the future.’