The west Londoners dominated the Group K tie from the offset as they avenged their controversial 1-0 defeat in Poland two weeks ago, while also extending their unbeaten home record in Europe to 22 matches.
Damien Duff handed Fulham an early lead by tucking away Andrew Johnson's low cross, but they were soon pegged back as an Andraz Kirm shot deflected in off John Arne Riise.
With in excess of 6,000 fans cheering on Wisla, there was a tense atmosphere at Craven Cottage due to Polish fans peppering the home end and a smoke bomb being let off.
However, Fulham continued undeterred on the pitch and regained the lead through Johnson's sublime volley on the 30-minute mark.
Johnson then extended the Cottagers' lead after a neat free-kick in the 57th minute, before substitute Steve Sidwell wrapped up the tie late on.
Heading into the clash, Fulham manager Martin Jol stuck to his word by naming a strong line-up for the Group K encounter.
Meanwhile, Wisla Krakow included Milan Jovanic, Marko Jovanovic and Ivica Iliev on the bench after they were cleared to play after visa issues.
The White Star came into the match on a poor domestic run and also had to cope without several key players in west London.
Such weakness was visible from the offset as Duff found time to strike an early shot that Sergei Pareiko did well to parry.
The Ireland international was not to be denied for long, though, as he broke the deadlock in the fifth minute.
Neat play down the right flank saw Johnson drill in a cross that Duff tucked away with ease.
But with a plethora of Polish supporters inside Craven Cottage the match felt like a home tie and they soon had something to cheer about.
Dudu Biton found space to run at the Fulham backline and, after a neat lay off by Lukasz Gargula, Kirm struck a shot that deflected in off Riise.
An enthralling opening 10 minutes continued as Johnson looked to put Fulham back into the lead, but the flick was ruled out for offside despite the tannoy announcer confirming the goal.
Jol's side continued to press forward in numbers looking to re-take the lead, with Clint Dempsey coming close to heading home a Duff corner.
Wisla were also looking dangerous and wasted a good chance from a counter-attack, failing to capitalise on a man advantage as Kirm blazed a cross over.
After several heavy challenges by both sides the noise rose inside Craven Cottage, Fulham returned to the attack and Riise saw a shot blocked wide by Cezary Wilk.
However, the home side regained the lead in the 30th minute when Danny Murphy teed up Johnson to volley home exquisitely.
Michael Lamey and Kirm then both had shots at the other end, before attention was focused off the field due to crowd disruption.
The number of Wisla fans in the home end were proving problematic and the away section then let off a smoke bomb that engulfed the whole pitch, although referee Halis Ozkahya allowed play to continue.
Clint Dempsey saw a cheeky chip clip the crossbar as half-time approached and the pitch cleared, before tempers began to flare as Bobby Zamora and Kew Jaliens both received yellow cards for coming head to head.
The second period started at a much slower tempo but both sides were still eking out chances.
Wisla were pushing forward in numbers but were caught out by a clever Fulham free-kick as Murphy laid off to Zamora, who flicked on to Johnson to dink over Pareiko from close range.
Temperatures began to rise again as the second half wore on with bookings handed out to both sides, with Gervasio Nunez enjoying his role as the villain.
The Argentinian midfielder was booed every time he touched the ball for his play-acting to get Mousa Dembele sent off in Poland and was guilty of simulation again on several occasions this evening.
Cheered on by the raucous away support, Wisla continued to pepper the Fulham goal and Jaliens saw a header rebound off the post.
However, the Dutch defender's header came moments after Sidwell fired home Fulham's fourth from close range after seeing his original header saved.
Fellow substitute Pajtim Kasami was the next to come close but Pareiko denied the Swiss midfielder with a fine save.