In came Andre Zambo Anguissa and Kevin McDonald as Jean Michael Seri and Ryan Sessegnon lost their places following Friday’s loss to West Ham.
It was a first start since October 27 for McDonald, who was sent off that day as Fulham lost 3-0 to Bournemouth at Craven Cottage.
They were hoping for a better showing against the Cherries’ south coast rivals, but the Whites were under pressure from the off.
Nathan Redmond was causing plenty of problems out wide, twice cutting in and going close with long-range strikes.
Southampton did have the ball in the net after 16 minutes, but Charlie Austin was judged to have fouled goalkeeper Sergio Rico in the build-up.
It looked a tad harsh and Rico’s goalkeeping was called into question again when Southampton did finally take the lead seven minutes later.
The Spaniard flapped at a corner and Romeu was on hand to drive the ball home from the edge of the box.
It was no more than Southampton deserved and despite Fulham showing signs of life, particularly through Aleksandar Mitrovic, they were 2-0 down five minutes before the break.
This time it was Ward-Prowse getting in on the act as the midfielder tapped home from five yards out as Rico could only parry Redmond’s shot.
It looked like a long way back for Fulham, who have not won an away game in the Premier League all season.
And the second-half duly followed the pattern of the first as Southampton again dominated proceedings.
It led to unrest among the 1,500 travelling Fulham fans, who unveiled a banner which read: “Slavisa. Making Fulham great again.”
Moments later another one was rolled out this time saying: “Risk free? Are you watching Tony Khan?”
On the pitch, the Whites continued to battle away but the closest they came to a goal was when Ryan Babel struck the crossbar with 16 minutes to go.
It means Fulham are 10 points from safety with just 10 games to go
