First-half goals from Jermaine Easter and Tommy Mooney were enough to send the League Two leaders into the third round of the Carling Cup for the first time in their history.
And despite Heidar Helguson making a game of it with a second-half header, Wanderers stood firm to earn a deserved win.
Chris Coleman made nine changes to the side that earned a goalless draw against Tottenham at White Hart Lane on Sunday.
And so many changes to the team showed in the Londoners' play.
Defenders Carlos Bocanegra and Moritz Volz were the only survivors as Coleman rotated the pack in a team, with keeper Jan Lastuvka, Gabriel Zakuani, Michael Timlin and Bjorn Runstrom making their full debuts.
And the home side were picking the ball out of the net as early as the seventh minute.
Easter fired home from close range for his ninth goal of the season, making him the most potent striker in English football.
It was the visitors who looked more like the Premiership side as they continued to grind out chances.
Mooney saw a left-foot shot sail high and wide before Fulham finally woke up.
Wayne Routledge's right-wing cross on 15 minutes found Helguson unmarked but his header was way off the mark.
Routledge looked like the only Fulham player who was causing problems and another right-wing cross again found Helguson on 34 minutes only for his weak toe-poke to be cleared off the line by Vincent Fernandez.
And a minute later, Fulham finally breached the visitors' defence only for Timlin's sliding shot from Routledge's short corner to hit the outside of the post.
Just when it looked like Coleman's men looked like getting back into it, Easter turned smartly in the box and forced Bocanegra into a needless challenge leading to a penalty.
Up stepped the veteran Mooney who made no mistake, sending keeper Lastuvka the wrong way to double the lead.
Mooney certainly had a taste for the big occasion and nearly added a third seconds later only for Lastuvka to push his dipping volley over.
Coleman's half-time teamtalk must have worked as Helguson soon reduced the arrears 60 seconds into the second half.
Runstrom's cross from the left found the Icelandic striker who headed in on the goal line.
Tomasz Radzinski fired wide ten minutes later before Runstrom blew a golden chance to level on 61 minutes.
A quick free-kick by Helguson sent Runstrom completely in the clear but the Swedish striker somehow fired wide much to the amazement of the home crowd.
Fulham applied some late pressure and brought on striker Collins John, but it was to no avail as defiant Wycombe held on for a memorable win.