The Bees' first win against Liverpool since 1938 was delivered through an own goal from Reds defender Ibrahima Konate and strikes from Yoane Wissa and Bryan Mbeumo at the Brentford Community Stadium.
Losing 2-0 at halftime, Jurgen Klopp rang the changes - including replacing central defender Virgil van Dijk - and Liverpool were given hope when Alex Oxlade-Chamberlain netted a 50th-minute header.
But Mbeumo pounced six minutes from time to kill the game off and end Liverpool's four-match winning streak in the Premier League.
"I can't say they surprise me, the players, but they keep impressing me," Brentford coach Thomas Frank told Sky Sports.
"It's a fantastic result for us in many ways but doing what we are capable of doing here against Liverpool is very impressive."
After early Liverpool pressure, Brentford took the lead after 19 minutes when Mbeumo's inswinging corner was diverted into the net by Konate.
Brentford's threat from set-pieces continued, with Wissa - in the side for injured talisman Ivan Toney - twice having the ball in the net, only for the offside flag to come to Liverpool's salvation.
Wissa would not be denied a third time though, heading home from Mathias Jensen's cross shortly before halftime.
Klopp made a triple-change at the break and it looked to have made an instant impact when Darwin Nunez lashed in, but a VAR check showed he was offside.
Liverpool did have one back shortly after when Trent Alexander-Arnold's sublime cross was met by Oxlade-Chamberlain on his 100th league appearance for the Reds.
Yet having weathered the storm, Brentford wrapped up a memorable victory with six minutes remaining, Mbeumo muscling Konate off the ball before drilling beyond Alisson.
"(It's) crazy, we know Liverpool are one of the best teams in the world so if you want to beat them you have to be at 100 per cent," Wissa said.
Liverpool manager Jurgen Klopp rued his team's early missed chances.
"It's a wild game, one Brentford wants," he said.
"I'm not sure you can really control it all the time because each corner is a massive threat.
"We conceded the first goal in the moment where we should already be 2-0 up - super chances from Darwin (Nunez) and Kostas (Tsimikas).
"It was more the game they wanted than we wanted. We have to accept that but, of course, we have to be much more clear in the situations where we are in control of the game."
The win moved Brentford into seventh in the Premier League, above west London neighbours Chelsea and two points behind sixth-placed Liverpool.
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