Despite a promising start, the visitors never really recovered after Kyle Ebecilio opened the scoring with the Gunners' first attack of the game after 13 minutes.
Chuba Akpom then made it two-nil just after the break, with Saints generally limited to half-chances on a frustrating evening in north London.
Martin Hunter was forced into three changes to the side that drew with Liverpool a week ago, but was able to call on three overage players to boost his squad.
Matt Targett and Alberto Seidi were ruled out through illness and injury respectively, while James Ward-Prowse was not selected after featuring for the First Team at Norwich on Saturday.
Danny Butterfield came in at right-back and, following the end of his loan spell at Bolton, Steve De Ridder was deployed on the right flank.
Vegard Forren was the third overage player in the starting line-up, keeping his place after scoring against the Reds on his first appearance for the Club last week.
Calum Chambers moved into midfield to cover for Ward-Prowse's absence, while Paulo Gazzaniga kept his place between the posts.
Saints started brightly despite the chilly conditions, with De Ridder seeing a low cross deflect just wide of the near post inside the opening 60 seconds.
Then, from the resultant corner, Omar Rowe's whipped delivery almost caught out Arsenal goalkeeper Damian Martinez but the Argentine hurriedly clawed the ball away from goal.
Rowe went close again on three minutes when the ball broke to him on the edge of the Gunners' box but his first-time shot flew just wide of the far post.
Instead it was the home side who broke the deadlock with their first attempt on goal. Saints conceded possession to Serge Gnabry in midfield, and the ball eventually found its way via Nico Yennaris to EBECILIO, who shot beyond Gazzaniga with 13 minutes on the clock.
Arsenal could have added a second midway through the half when Kris Olsson played in striker Akpom, but he fired over the Saints goal from a promising position.
Ebecilio had the opportunity to double his account on the half-hour when Conor Henderson's overhit cross was returned into the danger zone by Gnabry, but the Dutchman swept the ball over from close range.
There was a half-chance for Jake Sinclair to level ten minutes before the break when Gunners midfielder Olsson gave the ball away to him, but Elton Monteiro got back to block as the Saints forward took aim.
While it was the home side who had the better chances of the first half, it was Saints who dominated the possession without particularly troubling the Arsenal goal.
De Ridder did go close two minutes before the interval as he twisted and turned on the left side of the area, but his low shot flew just wide of the near post with Martinez at full stretch.
HALF TIME: ARSENAL U21S 1-0 SAINTS U21S
The first chance of the second half went Arsenal's way as the impressive Akpom jinked his way into the box five minutes after the break only to fire wide of the near post.
Saints coach Hunter immediately looked to shake things up with a double substitution, bringing on Joe Curtis and Lloyd Isgrove in place of Chambers and Rowe.
However, it was Arsenal who scored the game's second goal as Jack Stephens attempted to head Jordan Wynter's long ball back to Gazzaniga only for AKPOM to nip in before finishing confidently.
With little in the way of goalmouth action thereafter, Arsenal brought on Samir Bihmoutine and Nigel Spence-Neita with 20 minutes to go, while Saints threw on Sam McQueen for Sinclair moments later.
McQueen almost made an immediate impact when he lunged to latch onto Curtis's deflected shot, but Martinez was quick off his line to block from close range.
Moments before that, a fluid Arsenal move came close to making it three-nil but Gnabry ended the exchange by volleying wide of Gazzaniga's right-hand post.
Then, with less than a quarter-hour remaining, Saints almost halved the deficit as De Ridder snuck closer and closer to the Gunners goal only to be denied by an instinctive save from Martinez at the near post.
However, that was Saints' last meaningful attempt at getting a goal back on a frustrating evening in north London as their four-game unbeaten run came to an end.
FULL TIME: ARSENAL U21S 2-0 SAINTS U21S
Arsenal U21s: Martinez, Wynter, Angha, Monteiro, Meade (Bihmoutine 70), Yennaris, Henderson, Olsson, Ebecilio (Spence-Neita 70), Gnabry, Akpom (Mugabo 84). Subs (not used): Vickers (GK), Watt.
Goals: Ebecilio (13), Akpom (57)
Bookings: Angha (88)
Saints U21s: Gazzaniga, Butterfield, Stephens, Forren, Young, Robinson, Chambers (Curtis 52), Moore, De Ridder, Sinclair (McQueen 71), Rowe (Isgrove 52). Subs (not used): Johns (GK), Turnbull.
Referee: Lloyd Wood