Sam Hoskins gave Martin Hunter's side the lead after just 12 minutes, but the Black Cats hit back after the break through Jordan Laidler.
Calum Chambers headed Saints back in front just after the hour mark, before Hoskins' second of the afternoon put the home side firmly in the driving seat.
But Laidler added another 16 minutes from time to ensure Saints could not simply coast to victory, though they did hold on for a deserved three points.
With Lee Barnard and Jonathan Forte – who had featured heavily in the Under 21s' pre-season schedule – having departed for loan spells with Bournemouth and Crawley respectively, Hunter's starting XI had a slightly different look about it.
Hoskins moved into a central striking position, where he was supported by Jake Sinclair and Tadanari Lee on what was the Japanese's first start since returning from his foot injury.
Chambers was joined by Ben Reeves and Corby Moore in central midfield, while a defence of Danny Butterfield, Jack Stephens, Jordan Turnbull and skipper Ryan Dickson protected Cody Cropper's goal.
The first opportunity of the game arrived just after the 10-minute mark as Reeves worked space outside the Sunderland area, but his low drive flashed wide of Jordan Pickford's goal.
But Saints did not have to wait much longer for the opener as HOSKINS worked space on the edge of the area and clinically finished to give his side an early lead.
Kevin Ball's Sunderland could have levelled shortly afterwards as Ryan Noble got free down the left and centred across goal but Craig Lynch could not get on the end of his cross.
Hoskins had an opportunity to double his account when he drifted past goalkeeper Pickford and poked the ball towards goal only for John Egan to hack clear.
Billy Knott then saw two quick-fire attempts at the Saints goal kept out by some desperate defending, before Chambers teed up Hoskins to shoot narrowly over.
A smart free-kick routine by the Wearsiders almost drew them level as Laidler whipped the ball towards Cropper's goal, but his effort snuck narrowly wide.
An action-packed half began to draw to a close, though there was still time for a flowing move down the left to allow Chambers to tee up Dickson – but the left-back's shot ended up the wrong side of the crossbar.
Saints' first-half endeavours were not finished, though: Lee went close to scoring his second goal in as many games as he fired at goal from the edge of the box only to see his drive tipped around the post.
HALF TIME: SAINTS U21 1-0 SUNDERLAND U21
Saints were inches away from doubling their lead three minutes after the break as determined work by Hoskins down the right saw the ball fall invitingly in the centre for Sinclair, but his shot was deflected onto the crossbar by lunging defender Egan.
The hosts' luck worsened less than 60 seconds later as Laidler held off the attentions of Stephens and Turnbull before excellently finishing past Cropper to level.
Hunter's team were on the back foot for the next few minutes, but managed to restore their lead as CHAMBERS got on the end of Reeves' 63rd-minute corner to power home a header.
Happy with the forward's hour-long performance, the Under 21 Coach quickly decided to withdraw Lee and replace him with Sam McQueen, who impressed in pre-season wins over Sholing and Winchester City.
Saints moved into the ascendancy well following Chambers' goal, and doubled their advantage five minutes later as HOSKINS got on the end of Dickson's pass as converted smartly.
Substitute McQueen almost made a rapid impact when the ball broke for him on the right, but his low effort was tame and easily dealt with by Pickford.
His profligacy was punished on 74 as Sunderland right-back Louis Laing broke down the wing before squaring for Laidler to add his second of the afternoon.
Hunter sent on Joe Curtis in place of Sinclair as he sought to galvanise his team, and they could well have extended their lead before the match was out.
Hoskins had a golden opportunity to complete his hat-trick when he picked up Chambers' through ball and steadied himself to shoot from close range, but the impressive Pickford came out on top once more.
Nevertheless, Saints did manage to secure what was a worthy win to kick off their league campaign with a positive result.
FULL TIME: SAINTS U21 3-2 SUNDERLAND U21
Saints U21: Cropper, Butterfield, Stephens, Turnbull, Dickson, Chambers, Moore, Reeves, Sinclair (Curtis 76), Hoskins, Lee (McQueen 64). Subs not used: Johns (GK), Young.
Goals: Hoskins (12 & 67), Chambers (63)
Sunderland U21: Pickford, Laing, Egan, Ferguson (Joyce 89), Adams, Lynch, Oliver (Gorrin 70), Knott, Deacon (Mitchell 66), Noble, Laidler. Subs not used: Dixon (GK), Callaghan.
Goals: Laidler (49 & 74)
Referee: Adam Crysell
Assistant Referees: Garry Maskell & Sam Lewis