Nadal has won 86 career titles, including 35 in Masters events, but lost his only final at the Bercy Indoor Arena in Paris 13 years ago.
Thompson found his range in the second set, hitting a couple of big winners down the line and forcing a set point with Nadal serving at 6-5. After a decent second serve, Nadal saved it after a long rally.
Thompson threw his racket onto the ground in frustration after losing the next point, and Nadal’s sharp backhand volley at the net took it into a tiebreaker.
The unseeded Australian saved one match point with his third ace of the tiebreaker, but on the next opportunity, Nadal pushed his opponent to the back of the court and Thompson’s forehand sank into the net.
Nadal, a 20-time Grand Slam champion who on Wednesday became only the fourth man to reach 1,000 match wins, next faces Spanish countryman Pablo Carreno Busta.
Earlier, third-seeded Daniil Medvedev overcame a first-set blip where he conceded 11 straight points before rallying to beat 16th-seeded Alex de Minaur 5-7, 6-2, 6-2.
The strong-serving Russian concluded with a 13th ace and next plays No. 6 Diego Schwartzman, the French Open semifinalist who routed qualifier Alejandro Davidovich Fokina 6-1, 6-1 to take a step closer to reaching the season-ending ATP Finals for the first time.
“Diego is playing amazing at this moment,” Medvedev said. “His results are unbelievable.”
Schwartzman would qualify for the Nov. 15-22 tournament in London if he beats Medvedev.
Humbert knocked out French Open semifinalist Stefanos Tsitsipas in the second round and took his second title of the year two weeks ago at the European Open in Antwerp, Belgium.
Carreno Busta, who is challenging Schwartzman for a place at The O2 arena in London, won 7-5, 6-2 against unseeded Norbert Gombos.