The West Midlands outfit made the trip to Craven Cottage sitting in the bottom three of the Premier League table having only won once in their first 11 fixtures.
Their dismal start looked set to be extended when Alex Iwobi gave Fulham an early lead in West London, but that only acted as the catalyst for Wolves' best showing of the campaign.
Matheus Cunha and Joao Gomes scored either side of half time to complete the turnaround before Fulham running out of substitutions and being unable to replace injured centre-back Joachim Andersen worked in the visitors' favour.
During the closing stages, Cunha added his second of the game before Goncalo Guedes fired home deep into added-on time to earn Wolves a famous triumph in the capital.
What did O'Neil have to say?
Speaking to Match of the Day, O'Neil called on his players to "enjoy" the moment after a prolonged period of frustration since the middle of August.
That was in part to Wolves having just one fit centre-back, Mario Lemina having to drop into a deeper position to partner Toti Gomes with Craig Dawson and Santiago Bueno sidelined through illness and injury respectively.
The Englishman said: "I want the players to enjoy today. It was an incredible performance and I think we fully deserved the victory. Fulham are going to have a very good season, especially from 1-0 down.
"It was a tough run. We had a tough transfer window. Any club that organises its captain and one of its top players is going to have to find a new way. We had to bed in some young talent from different leagues. Then we had a really tough run of fixtures to start with, and our league position brings pressure.
"The next kick up the backside can come quickly. It's important the lads understand where this [win] came from. The organisation, togetherness gave us a real platform.
"I'm really pleased with everybody. Fulham have been excellent this season. When we suffered the injuries and illnesses we did, I feared what it might look like this afternoon."
Wolves are now on a four-match unbeaten streak in the top flight, accumulating eight points across that period.
That has O'Neil's side in 17th position in the Premier League table, although they will drop back into the bottom three if Ipswich Town overcome Manchester United on Sunday.
Next up for Wolves is an encounter against Bournemouth on November 30.