Caretaker boss Andy Awford said Portsmouth were shell-shocked after Will Atkinson and Barry Corr fired 10-man Southend to a 2-1 victory.
Five years ago Pompey were drawing 2-2 with AC Milan in Europe but they are now managerless and sitting five points above the relegation zone in League Two.
Andy Barcham fired in a 20-yard thunderbolt after 90 seconds to send Fratton Park crazy but the home side then missed chances to extend their lead.
After Cauley Woodrow saw red for an elbow on Jed Wallace the Shrimpers sprung into life and turned the game on its head, with Will Atkinson firing under Trevor Carson with 15 minutes to go before Barry Corr headed the winner soon after.
Awford said: "It has been a whirlwind. I wish we could reverse that decision and Guy still be here as it has been very difficult.
"I got the call and for me it is a proud moment to manage the club as a caretaker but I would give that away if Guy was still in charge as he is a good friend.
"I changed a few things from the team Guy was going to play which upset a few people but you live and die by those decisions.
"We should have been out of sight as we missed two fantastic chances to put the game to bed.
"We could have been four in front before they had a man sent off. You cannot keep conceding like we are and it is not good enough. I am majorly disappointed.
"All hell broke loose for a few minutes after their first goal and we are shipping far too many goals. At 1-0 the concentration has to remain."