The 28-year-old Tsonga, a semi-finalist in 2012, needed a medical time-out to have his left knee taped just after he had dropped the second set, 6-3.
Tsonga had won the first set, 6-3.
But when he dropped the third set 6-3, he gave up.
The French star was the seventh player to see his Wimbledon campaign ended by injury on Wednesday.
World number two Victoria Azarenka, Steve Darcis, who put out Rafael Nadal in the first round, and Marin Cilic all withdrew.
John Isner and Radek Stepanek both quit during their second round matches.
Just moments before Tsonga's retirement, Kazakhstan's Yaroslava Shvedova withdrew from her second round clash against 2011 champion Petra Kvitova, the eighth seed, with a right arm injury.
Results from the third day of Wimbledon (x denotes seeded player):
Men's singles:
Second round:
Lukasz Kubot (POL) bt Steve Darcis (BEL) - walkover
Adrian Mannarino (FRA) bt John Isner (USA x18) 1-1 - retired
Jerzy Janowicz (POL x24) bt Radek Stepanek (CZE) 6-2, 5-3 - retired
Viktor Troicki (SRB) bt Andrey Kuznetsov (RUS) 6-4, 6-3, 6-4
Lukosz Kubot (POL) bt Steve Darcis (BEL) - walkover
Kenny de Schepper (FRA) bt Marin Cilic (CRO x10) - walkover
Second round:
Monica Puig (PUR) bt Silvia Soler (ESP) 6-2, 5-7, 6-4
Carla Suarez Navarro (ESP x19) bt Mirjana Lucic (CRO) 1-6, 6-3, 6-3
Alize Cornet (FRA x29) bt Su-Wei Hsieh (TPE) 6-3, 6-2
Flavia Pennetta (ITA) bt Victoria Azarenka (BLR x2) - walkover