The France international, who scored two against the Saints when they met last Saturday, will join a three-pronged forward line alongside Eden Hazard and Willian as Antonio Conte attempts to steer his side into the final, where Manchester United await.
Morata, meanwhile, takes his place on the bench alongside the likes of Pedro and Tiemoue Bakayoko, who have also dropped out.
Thibaut Courtois has been replaced in goal by Willy Caballero, while Emerson reprises his role on the left flank in place of the suspended Marcos Alonso.
Nigerian winger Victor Moses, who scored in the last match against Burnley, is on the opposite side.
Cesc Fabregas returns to the starting XI to partner N'Golo Kante in midfield and Conte has retained the same back-line as the last outing, with Cesar Azpilicueta, Gary Cahill and Antonio Rudiger starting.
In all, Conte has made four changes from the team that defeated the Clarets during the week, with Courtois, Bakayoko, Pedro and Morata being replaced by Caballero, Fabregas, Willian and Hazard respectively.
Chelsea team: Caballero; Azpilicueta, Cahill, Rudiger; Moses, Kante, Fabregas, Emerson; Willian, Giroud, Hazard.
Subs: Eduardo, Christensen, Zappacosta, Bakayoko, Barkley, Pedro, Morata.
Southampton team: McCarthy, Cedric, Yoshida, Hoedt, Bednarek, Bertrand, Romeu, Lamina, Hojbjerg, Austin, Long
Subs: Forster, McQueen, Tadic, Redmond, Ward-Prowse, Gabbiadini, Carrillo.