Olivier Giroud scored directly after the restart and Alvaro Morata confirmed Southampton’s exit from the competition eight minutes from full-time.
Southampton, whose Premier League status remains a doubt with four games remaining, had rewarded fans with their second trip to Wembley in the last 14 months.
But fortunes didn’t change as Southampton hit the target just three times against a determined Chelsea side that dominated proceedings.
Southampton managed to escape from conceding in the opening 45 minutes, which kept the defence busy.
Eden Hazard twice came close to the game’s first goal inside a quarter-hour, but fired over the bar before being denied by a smart challenge from Maya Yoshida.
Mark Hughes’ men continued to be pressed back into their own half and Willian was kept at bay from a broken set piece as Cedric made a considerable effort to block a goalbound shot on 30 minutes.
Southampton was again left to hold their breath when Giroud’s acrobatic attempt cleared the bar six minutes from the interval.
But the forward -- known for his heroics when coming off the substitutes bench -- grabbed made it 1-0 to Chelsea 46 seconds after the second-half kick-off as he tucked in from close range after being played in by Hazard.
An immediate response from Saints wasn’t forthcoming, despite Shane Long trying to round a charging Willy Caballero on 54 minutes.
Long, who did well to get on the end of Wesley Hoedt’s pass, then took a heavy touch that guided the ball out of play nearing the hour mark.
Luck continued to be against Southampton, who nearly found an equaliser through Nathan Redmond with 18 minutes remaining.
Redmond’s 20 yard shot hit the underside of Caballero’s arm before skipping inches wide of the post.
Caballero nearly gifted Saints their way back into the match when he appeared to fumble the ball over the line from a corner kick, only for Charlie Austin to be adjudicated to have fouled the Chelsea keeper in the process.
Manolo Gabbiadini was thrown on for the final 12 minutes, but it was another attacking option for Chelsea that sealed Southampton’s fate.
Morata, who was introduced just moments before, nodded his header into the ground and into the net from Cesar Azpilicueta’s cross from the right-hand side.
It wasn’t to be for Saints with Austin striking the post before Hoedt cleared the ball off the line at the end other end as it reached full-time.
Chelsea: Caballero; Moses, Rudiger, Cahill (c), Azpilicueta, Emerson; Kante, Fabregas (Pedro 76), Hazard; Willian (Bakayoko 64); Giroud (Morata 80).
Unused subs: Eduardo (GK), Zappacosta, Christensen, Barkley.
Goals: Giroud (46), Morata (82).
Southampton: McCarthy; Cedric, Hoedt, Bednarek (Gabbiadini 78), Yoshida, Bertrand (c); Hojbjerg (Tadic 63), Lemina, Romeu; Long (Redmond 63), Austin.
Unused subs: Forster (GK), Ward-Prowse, McQueen, Carrillo.
Bookings: Yoshida (40), Romeu (50), Lemina (55), Hoedt (65).