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Doug Loft scored with a lucky late strike to preserve Gillingham’s unbeaten home record.
The Gills skipper came off the bench, having returned from injury, scoring a goal to level the game from 45 yards out.
Stephen McLaughlin had put Southend ahead in the first half before the Gills produced another late fightback.
Gills boss Justin Edinburgh made four changes to his starting XI, one of those enforced, as Josh Wright was suspended.
Jermaine McGlashan, Jordan Houghton, Brennan Dickenson and Ryan Jackson were all starters again on Saturday.
Gillingham were defending an unbeaten home record while Southend were looking to return to form, having lost 3-0 to Chesterfield in the week. A crowd just short of 7,000 was their best since the opening weekend.
Edinburgh’s men had produced a poor first half in their midweek game against Chesterfield and once again they struggled early on.
The Gills were struggling to keep possession and a mistake from John Egan led to the opening goal after 11 minutes. His sliced clearance fell to striker Joe Pigott and he nodded the ball into the path of Stephen McLaughlin, who finished well past Stuart Nelson.
Pigott, a former Gills loanee, was a handful for the home defence and he laid the ball off for McLaughlin to fire just wide as Southend looked for a second.
The Gills continued to struggle and when Jordan Houghton gave the ball away cheaply to Ryan Leonard, Nelson was forced into saving with his legs to deny Pigott.
It was a better end to the half for the Gills but they went off a goal down. A great challenge from Luke Prosser had denied Bradley Dack a shooting chance and Brennan Dickenson glanced a corner wide.
Edinburgh initially stuck with the same personnel and 4-2-3-1 formation for the second half but with an hour gone McDonald joined the action to partner lone-striker Donnelly upfront.
Southend man Gary Deegan was lucky to escape a second booking and a red midway through the half. Having already been cautioned, he hauled down Dack on the edge of the box, but escaped any punishment. Dack put the free-kick over the bar and Deegan was subbed straight away.
Chances remained in short supply for the Gills and Dack smashed a 20 yard effort narrowly wide of the post with 10 minutes left.
Visiting keeper Daniel Bentley made a great save to deny Harry Lennon from close range as the Gills pressed late on.
The Gills were level with a minute left. Loft floated the ball in from distance and with Daniels off his line the ball hit the back of the net.
Gillingham: Nelson, Jackson (Osadebe 82mins), Garmston (Loft 71mins), Egan, Houghton (McDonald 59mins), McGlashan, A Morris, Donnelly, Dack, Dickenson, Lennon. Subs not used: G Morris, Ehmer, Hessenthaler, Williamson.
Southend: Bentley, White, Bolger, Prosser, Coker, Leonard, Deegan (Atkinson 65mins), Wordsworth, McLaughlin (Weston 81mins), Pigott, Mooney (Rea 77mins). Subs not used: T. Smith, Worrall, Payne, O'Neill.
Attendance: 6,983 (1,378 away)