Isner started his season in Auckland and reached the quarterfinals, losing to the eventual champion Roberto Bautista Agut. At the 2016 Australian Open, he reached the fourth round for the first time in six years, defeating Spaniards Marcel Granollers and Feliciano López before losing to David Ferrer in straights sets. Instead of playing the US spring hardcourt tournaments, Isner decided to play two clay court tournaments in South America, losing his first match in both to Dusan Lajovic and Guido Pella, respectively. In the first round of the 2016 Davis Cup, Isner defeated Bernard Tomic and Sam Groth to help upset Australia 3–1 and move the United States into the quarterfinals against Croatia.