Thomas Frank’s side hit five second-half goals in west London to triumph 7-2 and jump to third in the second-tier table.
Brentford extended their remarkable unbeaten run to 18 matches and now sit just two points adrift of the automatic promotion places with a game in hand over both second-placed Swansea and leaders Norwich.
It was a competitive opening half at the Brentford Community Stadium, with Uche Ikpeazu and Leicester loanee Admiral Muskwe hitting back for Wycombe to ensure the score was level at 2-2 at the interval after Ethan Pinnock and Tariqe Fosu had twice given the hosts the lead.
However, the free-scoring Bees were fully unleashed after the break, with Fosu netting again early in the second half before top scorer Ivan Toney added another from the penalty spot after Fred Onyedinma fouled Sergi Canos.
At 4-2, Brentford were then kept at bay for 25 minutes until a late onslaught saw Canos and Josh Dasilva notch either side of a second goal from Toney, who reclaimed top spot in the Championship scoring ranks from Blackburn counterpart Adam Armstrong with his 18th of the campaign already.
A 15th league defeat of the season means Gareth Ainsworth’s Wycombe lie 24th and 11 points adrift of safety.
Elsewhere on Saturday, Swansea kept hold of second spot with a 3-1 win at Rotherham, while leaders Norwich were held to a goalless draw at home by play-off chasing Middlesbrough after Emi Buendia saw red in the second half.
Millwall drew 1-1 at Cardiff after Kieffer Moore’s effort cancelled out a first-half own goal from Aden Flint, while Wayne Rooney’s Derby overcame Bristol City and moved five points clear of the bottom three thanks to an early strike from Colin Kazim-Richards.
Blackburn are only three points shy of the top six after Armstrong’s 17th goal of the season five minutes from time saw off the spirited challenge of Luton, while Liam Palmer struck to secure a key victory for relegation-threatened Sheffield Wednesday against Preston.
There were 1-1 draws between St Andrew’s rivals Birmingham and Coventry and Huddersfield and Stoke, while both teams failed to break the deadlock in a stalemate between Nottingham Forest and Barnsley at the City Ground.
On Friday night, Reading beat top-six rivals Bournemouth 3-1 at the Madejski Stadium after a dominant first-half display.