The American player hit 21 aces but it wasn't enough against his Belgian opponent, who is enjoying an impressive season in which he is climbing the rankings. Goffin started the year at No. 175 and is currently ranked 45th.
Isner has gone 4-5 since winning in Winston-Salem in August, and will find his bid to qualify for the World Tour Finals next month severely limited with only the Paris Masters left to play before the season-ending event.
Seventh-seeded Marin Cilic joined Goffin in reaching the quarterfinals with a 6-1, 6-4 victory over Fernando Verdasco, with fellow Croatian Ivan Dodig also winning his second-round match, a 6-1, 3-6, 6-2 win over Australian veteran Lleyton Hewitt.
Gilles Muller of Luxembourg knocked off No. 8-seeded Milos Raonic in the first round, edging the Canadian 7-5, 7-6 (1).
Reigning champion Marcel Granollers of Spain also beat Czech qualifier Jan Hajek 7-5, 6-4 to advance to the second round.
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