The former England international had been in charge of the Shrimpers since October.
But he has now left Roots Hall along with Hermann Hredarsson, Andy Cole and Tony Colbert.
A spokesman for the club 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”
Sol Campbell added: “I have really enjoyed my time at Southend United Football Club, and whilst it was a difficult time fighting relegation, I still enjoyed the experience.
“We still managed to put together positive results, whilst also giving debuts to a number of the club’s talented young players.
“Southend have a great group of young players coming through from the academy, which was evident in our 3-1 home win against Bristol Rovers in our last game before lockdown.
“There are obviously frustrations with how the season ended abruptly, and with what points we feel could have been amassed.
“However, the club have an exciting future with the plans for the new stadium in place, but with the current global COVID situation having a profound effect on businesses, I am keen not to be a financial burden to the club.
“I also want to thank the fans for their support throughout my time at Southend and wish the club and all the support staff the very best for the future.”