Freddy Eastwood scored his first goal since rejoining Southend as 10-man Cheltenham were swept aside.
Sido Jombati was shown a straight red card for a lunge on Michael Timlin before the hosts went ahead when Kane Ferdinand turned in Ryan Hall's cross.
Hall added the second with a low strike from 30 yards, before Eastwood extended the lead with a deflected effort.
Bilel Mohsni rounded off a fine evening for the Shrimpers with a superb strike from 25 yards to make it 4-0.
The result saw Southend strengthen their League Two promotion credentials in fourth position, now just one point behind third-placed Crawley.
Cheltenham sit in seventh place, four points ahead of Crewe, who have played one game fewer.
In his first home start since returning on loan from Coventry, Eastwood's first game at Roots Hall for five years turned into Southend's biggest home win of the season.
Cheltenham suffered an early blow when referee Trevor Kettle had no hesitation in sending off Jombati for his foul on Timlin after 19 minutes.
And it took nine minutes for the 10-man visitors to go a goal behind when Hall's cross from the left was nodded on by Eastwood to Ferdinand at the back post and he fired into the bottom left corner from five yards.
Southend doubled their lead on 39 minutes when Hall cut in off the right wing and unleashed a 30-yard rocket which went into the centre of Jack Butland's goal after the keeper misjudged the shot.
Eastwood made it 3-0 on 51 minutes when he latched onto an upfield Hall punt, beat lan Bennett and saw his deflected shot find the top-left corner.
And Butland was beaten for a fourth time on 67 minutes when he failed to deal with Mohsni's 25-yard effort which went straight down the middle.
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Southend manager Paul Sturrock told BBC Essex:
"It [the win] was huge. People will say ten men all of sudden changed the game, but we were very confident when it was eleven versus eleven we would have gone on to win the game.
"It was a very, very thoughtful performance after they went down to ten men. They [the players] did the right things.
"They spread the ball round, they came down one wing to go to the other wing, we got lots of crosses in the box.
"We shared the load of scoring the goals as well. I'm very pleased."
Cheltenham Town manager Mark Yates told BBC Gloucestershire:
"Too many used the excuse of Sido Jombati's sending off to concede goals and not do enough. We're better than that.
"Sido has made a big mistake. He's made a rash, stupid decision and he didn't need to do it. I've seen teams win with 10 men and be gritty and determined with 10 men but we allowed it to be too easy.
"We gifted them the first goal and Jack [Butland] has not had the best of times for the others. It's a night to forget for him.
"We have six games left and there's no point moping. The players know how angry I am but we have to move on quickly.
"We're seventh and we've got to make sure we stay in the play-offs. We can definitely do it but we have to be better than we were for 75 minutes."