Brentford defeated their London rivals 3-1 thanks to a second-half brace from Bryan Mbeumo, further deflating Tottenham's underwhelming season.
Spurs had the ideal start in their pursuit of remaining in the running for Europa League football thanks to Harry Kane's early goal, but the visitors turned the tables with an excellent second half performance.
Ivan Toney, who was given an eight-month suspension from all football activity by the FA on Thursday for betting violations, was replaced by Mbeumo, who quickly collected a quickfire brace.
Later, Thomas Frank's team won thanks to a goal from Yoane Wissa, handing Spurs their 14th loss in the Premier League, while fans continued to call for club chairman Daniel Levy to resign as they left the field.
The club's dismal mood had been exacerbated by Tottenham's defeat at Aston Villa the previous weekend, but the sun was shining for this season's final home game, and Ryan Mason rang the changes.
Attackers Arnaut Danjuma and Dejan Kulusevski were recalled, and Yves Bissouma, who has recovered from injury, had his first start since January as acting head coach of Spurs adopted the 4-2-3-1 formation he had previously employed in 2021.
Chairman Levy acknowledged the difficulties of the season in his program notes but pledged to bring "on-pitch success" following a disorganized campaign.
Kane's long-term future at Spurs is one of Levy's many important decisions this summer, along with the selection of a new head coach and managing director of football.
The vice-captain of Tottenham gave another reminder of his significance after eight minutes.
Kane's 30th goal in all competitions was assisted by Kulusevski after Oliver Skipp, another academy graduate, won a free kick about 25 yards away. Kane curled the ball over the wall and beyond David Raya.
Son Heung-min was the next to go close, but Raya stopped him following Kane's pass, giving the hosts the perfect start.
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