Isner, the top-seeded defending champion at Newport, R.I., brushed past the Frenchman 6-2, 7-6 (7-2) in a second-round match-up.
The two played each other in a 2010 opening-round Wimbledon meeting that stretched over parts of three days and ended as the longest-ever men's tennis match.
The 6-foot-9 American eventually prevailed in that struggle. He improved to 3-1 lifetime against Mahut Wednesday.
In other Day 3 action, No. 2 seed Kei Nishikori of Japan breezed past two-time Newport runner-up Olivier Rochus, 6-7 (6-8), 6-4, 6-2, while Israeli Dudi Sela bounced Sam Querrey of the United States 5-7, 7-6 (8-6), 6-2.
Also advancing was 2009 champ Rajeev Ram, who logged a win over fellow American Michael Russell, 7-6 (8-6), 6-3. South African qualifier Izak Van der Merwe moved on with a 6-4, 6-4 victory over American wild card Jack Sock.