He started his second-round rout by breaking Istomin twice in the opening set and cruised into Friday's quarterfinals at the inaugural tournament in Johannesburg.
"I played well against an opponent who was not easy to overcome and I'm finding no problem with the altitude," Tsonga told reporters.
Other winners included Tsonga's opponent in the quarters, seventh-seeded Kristof Vliegen of Belgium, a 6-4, 6-1 winner over Czech Ivo Minar; No. 4 Guillermo Garcia-Lopez of Spain, who topped Argentina's Leonardo Mayer 6-4, 7-5; No. 5 Jeremy Chardy of France, a 6-4, 6-4 winner against Switzerland's Marco Chiudinelli; Portugal's Frederico Gil, a 4-6, 7-5, 6-4 victor against local favorite Rik De Voest; and France's Sebastien De Chaunac, who beat South Africa's Izak Van der Merwe 6-7 (3-7), 7-5, 7-6 (7-5).
Sunday's champion will pocket $79,000.
Swim Week Miami Beach 2014 [PHOTOS]