The midfielder was in fine form with the first team on our tour of the USA and Canada before being laid low with a calf injury in the week leading up to the home friendly against Schalke.
Mason pulled the strings with Harry Winks in midfield - especially as we controlled the first half - and opened the scoring with a classy strike on 26 minutes.
Ryan Seager replied against the run of play two minutes later before a penalty from Emmanuel Sonupe on 31 minutes and Daniel Akindayini's clinical finish after 75 minutes put us 3-1 up.
Saints reduced arrears again five minutes from time via Seager's second goal and that's how it stayed as we made it two wins in two this season.
It was a fast-flowing, snappy affair with both teams looking to get the ball down and play.
The first chance arrived after just three minutes when Sonupe's shot was spilled by Cody Cropper but the goalkeeper recovered to gather the loose ball.
Oduwa was twice wide of the target before Mason fired inches over after Kyle Walker-Peters' burst down the right. The young right-back - named Player of the Tournament as our Under-18s won the Premier League Champions Cup last week - impressed on his Under-21 debut.
Walker-Peters was there again to set-up Josh Onomah, his shot blocked, and the same player dragged wide of the target on 20 minutes.
Mason hit a dipper that grazed the roof of the net and it was no surprise when we opened the scoring on 26 minutes.
Nathan Oduwa started it by making progess down the left and squaring to Onomah, who simply helped it on to Mason who let the ball run across him before firing out of the reach of Cropper into the corner, a difficult technique made to look easy.
It was a surprise, however, when the Saints responded inside two minutes.
There was a stroke of fortune about the goal as well as the ball fell kindly to Seager in the box and the striker made no mistake from six yards.
It took just three minutes for us to restore the lead and it was Walker-Peters causing havoc again down the right, this time clipped by Josh Debayo in the box and referee Mr Kelly pointed to the spot. Sonupe made no mistake, finding the bottom corner.
Akindayini sent a shot just wide from the left angle on 41 minutes and McGee was forced into his first save of note a minute later, tipping over Seager's looping header. Southampton had the final word of the half as McGee saved Harley Williard's shot down to his right.
The second half was a much quieter affair in front of goal and we had to wait until the 71st minute for the next action of note as McGee produced the save of the night to tip over Jake Flannigan's free-kick destined for the top corner.
Four minutes later and we were 3-1 up. Alex McQueen broke down the left and fed Oduwa, he found Akindayini and the striker strode into the box before slotting home from the left angle.
Substitute Ruben Lameiras let fly from 25 yards, his shot fizzing a couple of yards wide but Saints weren't giving it up and responded again when Seager converted Flannigan's low cross on 85 minutes.
Both teams went close in the final minutes - Akindayini and Lameiras just off target and Josh Sims' shot in the 92nd minute deflected just wide.
Spurs U21: McGee; Walker-Peters, Ball, Veljkovic, McQueen; Mason (Lameiras, 59), Winks (Lesniak, 68); Sonupe (Miller, 78), Onomah, Oduwa; Akindayni. Substitutes (not used): Voss, McEneff.
Southampton U21: Cropper, Mason, Debayo, Flannigan, McCarthy, Wood, Sims, Hesketh, Seager, Rowe, Williard (Regis, 59). Substitutes (not used): Johns, Little, Barnes, Cook.