Wanderers found it tough going breaking down their Premier League opponents and the visitors secured victory through Mladen Petric’s first-half goal and efforts in the final five minutes from Bryan Ruiz and Steve Sidwell.
Petric had the first effort of the game in the 14th minute, but he dragged his shot wide of Nikki Bull's left-hand post.
However, the striker made no mistake three minutes later when he was given too much space 20 yards out from goal and powerfully fired past a helpless Bull.
Petric was proving the main threat to the Wanderers and Grant Basey produced a fine challenge to prevent him going through on goal.
Wycombe struggled to pose much of an attacking threat in the first half, but Stuart Beavon and Sam Wood, on his home debut, both looked lively.
Chairboys’ first effort came 10 minutes before the break when Fulham failed to deal with a free-kick and Stuart Lewis shot over the bar from the edge of the area.
Buomesca Tue Ne Bangna came close to doubling the lead four minutes later, but he curled a strike over the bar following neat play from Mahamadou Diarra, Moussa Dembele and Petric.
Bull was called into action shortly before the break and did well to save Petric’s curling free-kick, which was destined for the bottom-right corner.
Alex Kacaniklic shot straight at Bull five minutes into the second half and Wycombe’s keeper made himself big to deny Ne Bangna after the youngster was played in on goal.
Lewis crashed an effort over the bar just before the hour and John Arne Riise wastefully shot over when well placed.
Bull produced a fine stop to tip Bryan Ruiz’s chip over the bar after Steve Sidwell had intercepted Gary Doherty’s pass.
Diarra tested Bull again in the 68th minute, but he was more than equal to the task and parried the long-ranger away for a corner.
Bryan Ruiz added a second for the visitors five minutes from time when he curled an unstoppable 25-yard free-kick past Bull before substitute Steve Sidwell slid in Sascha Riether’s cross two minutes later.
Wycombe: Bull, McCoy, Basey (Dunne 63), Doherty, Stewart (Johnson 63), Oli, Lewis, Spring (Bloomfield 63), Wood (Angol 74), Beavon (Grant 63), Logan (McClure 74)
Fulham: Schwarzer, Riether, Riise, Hughes, Hangeland, Dembele (Trotta 76), Diarra, Mesca, Ruiz, Kacaniklic (Sidwell 59), Petric (Frei 59).
Subs: Somogyi, Burn, Pritchard, Kelly, Etuhu.Attendance: 1711