The No 2-seeded Isner beat Tunisian Malek Jaziri 6-3 3-6 7-6 (8-6) to ensure at least one of the tournament's main drawcards has survived past the second round.
His win comes after defending champion and top seed Roberto Bautista Agut earlier withdrew with a stomach bug, while No 3 seed David Ferrer crashed out.
Isner overcame a serving display that was disappointing by his own standards to hold his nerve in yet another tense tiebreak on Auckland's centre court this afternoon.
Crucially, Isner made headway against opponent Jaziri's serve at just the right time to claim victory in the decider, having earlier struggled for almost two sets.
No 56-ranked Jaziri by contrast will be disappointed not to have walked away with a big scalp.
After losing the first set, he spent much of the rest of the match outshining Isner.
Jaziri not only came close to breaking Isner early in third set with a series of blistering passing shots when the big American approached the net, he also put in a stellar serving display.
This was highlighted by the fact that after taking the second set Jaziri had not only levelled the ace count with Isner at nine a piece but won more points on his first serve.
Unfortunately for Jaziri, when it came to the tiebreak, it was Isner with his extra 23cm in height whose serve held up under pressure as he claimed the win.
Isner now meets compatriot Steve Johnson in the quarterfinals after he beat Taiwanese veteran Yen-Hsun Lu 6-4 7-6 (7-4).
