Tsonga produced an excellent performance to eliminate the Wimbledon champion 6-2 6-2 in just an hour and three minutes.
Having been defeated by Djokovic in the last 16 at the French Open and Wimbledon this year, Frenchman Tsonga will have not needed any further motivation to earn his sixth win in 19 meetings with the Serbian.
The world number 15 proved too hot for Djokovic to handle, Tsonga's blistering display featuring 23 winners, which enabled him to break the top seed on four occasions.
The victory ended Tsonga's 11-match losing streak against Djokovic, a run that had stretched back to the 2010 Australian Open.
Afterwards Djokovic conceded that the better player had emerged victorious.
"Congratulations to Jo," Djokovic said. "He played some great tennis. Served very well. He was obviously the better player on the court.
"I hadn't played even close to what I intended before going to the court. Just nothing was going. No baseline, no serve, no return. Generally a very bad day, very poor performance. Couldn't do much."
While Djokovic suffered an early exit, his predecessor as Wimbledon champion, Andy Murray, was given a free pass through to a quarter-final meeting with Tsonga.
Murray's scheduled third-round opponent Richard Gasquet withdrew due to an abdominal strain, handing the Brit an extra day of rest as he seeks to regain the title he won in consecutive years in 2009 and 2010.
Swiss second seed Roger Federer survived a scare on his way to a 7-6 (7-5) 6-7 (3-7) 6-4 win over Croatian Marin Cilic.
Cilic, the 15th seed, battled hard during the second set – saving six match points – but suffered his fifth loss in as many matches against Federer.
Grigor Dimitrov, Murray's conqueror in the Wimbledon quarter-finals last month, emerged victorious 7-5 5-7 6-4 from an enthralling contest with Spain's Tommy Robredo.
The Bulgarian saw off a spirited fightback from Robredo to keep his hopes of a first ATP Masters 1000 title very much alive.
Dimitrov will take on Kevin Anderson in the last eight after the South African served 11 aces in a shock 7-6 (8-6) 7-5 victory over third seed Stanislas Wawrinka.
In-form Canadian sixth seed Milos Raonic sent down 15 aces in his 6-3 4-6 6-4 win over Frenchman Julien Benneteau.
Awaiting Raonic in the last eight is Feliciano Lopez after the Spanish left-hander upset Czech fourth seed Tomas Berdych 3-6 6-3 6-4.
Fifth seed David Ferrer survived a scare to book his place in the quarters, coming from behind after a dismal first set to beat Ivan Dodig 1-6 6-3 6-3.