Nadal, the No. 2 seed, will take on fourth-seeded Andy Murray in the semifinal round after Murray rallied to defeat Janko Tipsarevic 4-6, 6-3, 6-4.
In their first meeting of the year, Nadal finally put the win away Tsonga on the third match point and recorded a 6-2, 5-7, 6-4 decision. Tsonga had won two of the three matches against Nadal last year.
Murray, the 2009 champion of this event, shook off an upset stomach and a stiff Florida breeze to prevail at Crandon Park.
Nadal has a 13-5 career record against Murray, but Murray ended a five-match losing streak to Nadal when they met in Tokyo last year.
The two other semifinalists will be determined Thursday when top-seeded Novak Djokovic plays No. 5 David Ferrer and eighth-seeded Mardy Fish takes on 21st-seeded Juan Monaco.