The French Open and U.S. Open champion has won five titles this season and is closing in on the year-end No. 1 ranking.
He is now an ATP World Tour-best 59-9 (32-7 on hard courts) in 2017 and continues his quest for a 75th tour-level crown.
Rafa saved all three break points he faced against Isner. He will next play third-seeded Grigor Dimitrov, who defeated Roberto Bautista Agut 7-6 (5), 4-6, 6-2.
Source: AP, Photos: Getty Images