Brendan Galloway, who has made 19 first-team appearances for the Toffees this season, opened the scoring ten minutes before half time.
Sam Byrne added a second just before the break as the hosts dominated the opening 45 minutes at Finch Farm. A wondergoal from Kieran Dowell made it 3-0, before Armani Little grabbed a consolation for Saints on a freezing cold evening in Liverpool.
With six regulars out on loan in the Football League and a number on the treatment table, Martin Hunter named an extremely young side for the trip to Finch Farm.
15-year-old Jake Vokins made his first start for the Under-21s following his impressive display in the 1-1 draw with Tottenham Hotspur, while Richard Bakary made only his second start at this level at right-back.
Saints’ inexperienced back four was under pressure from the off, with Courtney Duffus volleying just over from Dowell’s cross before Joe Williams fired narrowly wide.
Paulo Gazzaniga’s experience showed shortly after as he saved excellently from Duffus, who was causing plenty of problems for the Saints defence with his movement.
An experienced Everton side was enjoying the majority of possession, and but for Gazzaniga would have been ahead just after the 30-minute mark.
The goalkeeper did superbly to tip away long-range strikes from Dowell and Bryne as the hosts continued to press in front of Everton first-team boss Roberto Martinez.
Gazzaniga was finally beaten 11 minutes before half time as Duffus crossed to the back post where Galloway was waiting to fire home from a narrow angle.
Everton almost doubled their lead in identical circumstances moments later, but Gazzaniga produced a stunning stop to deny Byrne and keep Saints in the game.
Saints needed the break to compose themselves, but on the stroke of half time Everton found a second. Byrne was afforded time in the penalty area after a clever short-corner routine and he smashed home.
Everton thought they had made it 3-0 right at the start of the second half, but Callum Connolly was adjudged to be in an offside position as he headed beyond Gazzaniga.
The third goal did come just before the hour mark, as Dowell saw Gazzaniga off his line and lobbed the Saints goalkeeper from over 35 yards.
Saints had been unable to really threaten the Everton backline, but four minutes later they pulled one back. Little was on hand to slam home a cross from Jake Hesketh to give the visitors hope.
The goal proved little more than a consolation for Hunter's side, who will now look to bounce back at home to Reading.
Everton Under-21s: Russell Griffiths, Gethin Jones, Matthew Pennington, Callum Connolly, Brendan Galloway, Tom Davies, Joe Williams (c), Harry Charsley, Sam Byrne (Callum Dyson 82), Kieran Dowell (Antony Evans 90), Courtney Duffus (Matthew Foulds 86).
Unused substitutes: Lewis Gray (GK), Morgan Feeney.
Goals: Galloway (34), Byrne (45), Dowell (59)
Southampton Under-21s: Paulo Gazzaniga (GK), Richard Bakary, Ollie Cook, Alfie Jones, Jake Vokins (Thomas O’Connor 84) Harrison Reed, Armani Little, Josh Sims (Olufela Olomola 64), Dom Gape (c), Jake Hesketh, Sam Gallagher.
Unused substitutes: Harry Lewis (GK), Tyreke Johnson, Harley Willard.
Goal: Little (63)
Booked: Reed (66)