The Cottagers were condemned to the Championship next season following a heavy defeat at the Britannia Stadium, where goals from Odemwingie, Arnautovic & Assaidi did the damage
The Cottagers conceded three times in the second half and despite Kieran Richardson's consolation, ultimately fell to a 4-1 defeat to the Potters.
Felix Magath had never previously suffered relegation during his managerial career, but the German's impressive record came to an end as his men were swept aside by rampant Stoke in a one-sided Premier League clash.
Sunderland's victory at Manchester United ensures the London club's 13-season stay in the top flight is over and the manner in which they were beaten at Stoke will have been difficult to take for Fulham's supporters.
Peter Odemwingie opened the scoring with his sixth goal since his move from Cardiff City, whose relegation was also confirmed on Saturday.
|VIEW FROM BRITANNIA STADIUM
|By Greg Taylor
Stoke were superb, goals from Odemwingie, Arnautovic, Assaidi and Walters capped a fine display and ensures they finish in the top half of the Premier League table for the first time.
Fulham on the other hand were desperately poor all afternoon. They were beaten on the break by Stoke's rapid passing and direct play, with Assaidi, Odemwingie and Arnautovic all playing brilliantly.
After 13 years Fulham are relegated and will be playing Championship football next season.
Marko Arnautovic doubled Stoke's lead in a game that they dominated from start to finish and the impressive Oussama Assaidi added a third goal.
Kieran Richardson did reply for Fulham, but Stoke substitute Jon Walters swiftly made it 4-1 to compound Fulham's misery.
Hughes, who walked out on Fulham in 2011, is on course to guide Stoke to their first top-10 finish in the Premier League, while his former employers must prepare for life in the second tier.
Assaidi was named in the Stoke starting line-up for the first time in almost three months after a spell on the sidelines with a knee problem and ought to have put his side in front just two minutes in.
Steven N'Zonzi cut the ball back for the on-loan Liverpool winger, who came in the expense of Peter Crouch, but Assaidi blazed wildly over the crossbar with his right foot.
Mahamadou Diarra breathed a sigh of relief when he gifted the ball to Stephen Ireland 25 yards from his own goal and David Stockdale spared his blushes with a fine reflex save.
Assaidi was a constant menace to the Fulham defence and the busy Stockdale had to be alert to keep out the Moroccan's long-range drive as Stoke set a frenetic pace.
Lewis Holtby made way for Ashkan Dejagah shortly after only 34 minutes, but Magath's attempt to turn the tide failed to have the desired effect.
Stoke were dominant and it came as no surprise when they moved in front six minutes before the break.
Arnautovic was the architect as he cut the ball back for Ireland. The midfielder's shot took a deflection before hitting the crossbar and dropping down nicely for Odemwingie to slot home.
Fulham were unable to live with the home side's passing and movement and Stockdale produced another fine save to thwart the influential Arnautovic.
The Austrian was not to be denied nine minutes after the break, though, as he finished off a brisk Stoke break to double their lead.
Assaidi found Odemwingie with a sublime pass and the Nigerian this time turned provider as he picked out the onrushing Arnautovic, who beat Stockdale with a clinical right-footed finish at the back post.
Assaidi had the bit between his teeth and rounded off another rapid break after Arnautovic had squared from the right 73 minutes in.
Substitute Richardson pulled a goal back with a right-footed finish from inside the penalty area 10 minutes from time, but the damage had already been done.
And Walters completed the scoring when he slotted home a fourth Stoke goal with eight minutes remaining to add insult to injury for Magath's men.