Second-half goals from Rickie Lambert, Adam Lallana and Jay Rodriguez put Rene Meulensteen's side to the sword at Craven Cottage.
Mauricio Pochettino's men produced a magnificent second-half display to seal their first win at the home of the London club for over 66 years. The result condemned Fulham to a fourth straight top-flight defeat and left Rene Meulensteen's side three points adrift of safety at the foot of the table.
Southampton took the lead just after the hour mark as Adam Lallana marked his 250th appearance for the club with a goal.
From there, Fulham's resistance wilted, with Southampton's lead doubled after 70 minutes through Rickie Lambert's simple finish.
|VIEW FROM CRAVEN COTTAGE
|By Oliver Platt
In the end, a comfortable victory for Southampton clinched in style - but it could have been so, so different. Fulham was the better side in the first half but failed to take its chances - Darren Bent will again take flak but he did not have much support - and the Saints made Fulham pay after the break with an outstanding display of quick, precise counterattacking.
Roy Hodgson should tune into Match of the Day tonight for three goals created and scored by Adam Lallana, Rickie Lambert and Jay Rodriguez. Three Lions in the true sense of the phrase.
Fulham, which handed debuts to new signings William Kvist and Lewis Holtby, spent much of the opening stages on the back foot and almost fell behind as Maarten Stekelenburg was forced into a reflex save after Steve Sidwell had turned Rodriguez's cross towards his own net.
Meulensteen's men soon responded, though, and would have taken the lead if not for Artur Boruc, who produced a fine stop to keep out Brede Hangeland's close-range header.
Still, Southampton enjoyed the better of the play, midfielder Morgan Schneiderlin drawing another strong save from Stekelenburg before Maya Yoshida glanced a header wide.
Most of Fulham's threat came via striker Darren Bent, who was twice denied by Boruc shortly before the interval, first from a left-footed volley and then from a near-post effort after the on-loan Aston Villa striker had broken free of the Southampton defense.
Southampton brought on Jack Cork in place of Victor Wanyama at halftime and the visitors almost broke the deadlock early in the second half, as Schneiderlin's spectacular overhead kick flew just over the crossbar.
Lallana then tested Stekelenburg but Fulham failed to heed that warning, affording him the space to put Southampton ahead after 64 minutes.
The England midfielder drilled home a superb left-footed finish after latching on to a perfectly placed through-ball from Lambert.
Southampton gained in confidence following the goal, Steven Davis and Schneiderlin both seeing goal-bound efforts blocked.
And the inevitable second soon arrived as Lambert netted his eighth of the season. Lambert had the simple task of slotting home from close range after Nathaniel Clyne's low cross had found the striker unmarked in the area.
Pochettino's team refused to take its foot off the gas, though, as Rodriguez applied the gloss to a fine display 15 minutes from time. The ex-Burnley man cut on to his right foot and curled past a despairing Stekelenburg and into the top corner.