The visitors came into the game on the back of a four-game winning run and wasted no time in opening the scoring, with Jack Payne netting in just the second minute.
But Wycombe staged a fantastic turnaround for the sixth time this season, as Paris Cowan-Hall, Joe Jacobson and Matt McClure (two) secured their biggest home win of the campaign.
Gareth Ainsworth made three changes to his side, with Alfie Mawson and Cowan-Hall available again after missing last week’s FA Cup tie, while McClure started in place of Steven Craig in attack.
But they started in the worst possible fashion when Southend – cheered on by an away crowd of over 1,000 fans – opened the scoring inside two minutes. Myles Weston took advantage of room down the right to deliver a perfect cross to Jack Payne, who had enough time and space to fire home past Matt Ingram.
It was a nervy and unassured start from the hosts, who struggled to keep possession on a bobbly pitch, but came inches away from an equaliser when Peter Murphy rattled the bar from 20 yards after Dan Bentley had parried Matt McClure’s shot into his path.
Sam Wood then volleyed over from 20 yards as Wanderers gradually got a hold of the game, and it seemed that centre-backs Luke Prosser and Cian Bolger were going to win most of the aerial balls so the Chairboys needed a more inventive approach on the ground.
However, it was a direct approach which got them back into the game when Aaron Pierre stood his ground to chest a high ball down into the path of Paris Cowan-Hall, who smashed home a half-volley for his third goal in as many games.
The leveller seemed to bring to an end a good attacking spell from the hosts as the game developed into more of a midfield battle before the interval, but Wanderers found themselves ahead with just a few seconds remaining as Southend switched off at a crucial time.
Joe Jacobson’s quick throw found Peter Murphy in space and he threaded a clever pass out to Sam Wood, who drilled a low cross into the six-yard area and the ball was forced home by Matt McClure from just a couple of yards out.
Wycombe hadn’t scored a first half goal from open play at Adams Park all season but found themselves with two in the opening 45 minutes, before United made two changes at the break with Gary Deegan and Kevan Hurst replacing John-Joe O’Toole and Myles Weston.
The subs gave the visitors new impetus as they started the second period strongly, and David Worrall bent a free-kick over the bar before testing Ingram’s handling at his near post.
But the game got away from them when Jerome Binnom-Williams was shown a straight red card for a foul on Josh Scowen, giving the Shrimpers a mountain to climb – and it was about to get tougher.
Dan Bentley denied Matt McClure with a smart block inside the area but he was helpless moments later as Joe Jacobson curled home a beautiful free-kick from 25 yards, making it 3-1 – Wanderers’ most common scoreline of the season.
But they went one better on 72 minutes when McClure belted home the fourth goal with a stylish finish from 20 yards, bringing Adams Park to its feet as the points were all but secured.
Fred Onyedinma fired wide from a tight angle on his home debut, and curled one over the bar in the final six minutes, before the game reached its conclusion to keep the Blues on top of League 2.
Wycombe: Ingram, Jombati, Jacobson, Mawson, Pierre, Cowan-Hall (Onyedinma 80), Murphy, Scowen, Wood, Hayes (Holloway 80), McClure.
Unused subs: Richardson, Rowe, Lewis, Bloomfield, Onyedinma, Craig, Holloway.
Southend: Bentley, Leonard, Binnom-Williams, Prosser, Bolger, Worrall, Timlin (White 66), O’Toole (Deegan 45), Weston (Hurst 45), Payne, Corr.
Unused subs: Smith, Atkinson, Clifford, Coulthirst.
Attendance: 4,123 (1,089 from Southend)
Winning 50/50 Draw Number: 123265
Prize Money: £609.00