Andy Murray was slain by a giant as he failed to reach the third round of Wimbledon for the first time in his career.
And even though he went to the well and briefly threatened to pull off another epic comeback, there was no fairytale ending this time on Centre Court.
The 35-year-old former world number one clinched the third set to keep alive his hopes but fell 6-4 7-6 (7-4) 6-7 (3-7) 6-4 to the big-hitting 20th seed.
Isner, a 2018 semi-finalist, fired 36 aces on his way to an impressive victory on Centre Court.
He will play 20-year-old Italian 10th seed Jannik Sinner next.
Murray had never before failed to reach the third round at SW19, in 13 previous attempts.
Murray, whose Wimbledon preparations were disrupted by an abdominal injury, had come back to win his opening match against Australian James Duckworth on Monday in four sets.
A fightback was once again required against an opponent he had beaten in all eight previous meetings, but Isner proved an insurmountable obstacle in their first contest on grass.
Isner was magnanimous towards his beaten opponent in his on-court interview, saying: “I am most definitely not a better tennis player than Andy Murray, I might have just been a little better than him today.
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