The Spaniard got off to a confident start, taking the first set 6-3.
A hard-fought second set resulted in a tie break, which Isner took 7-6(3).
The American could not build on his second-set win, however, and 18th seed Lopez captured the third 6-4.
The fourth set went with serve to force a tie break, which again went in favour of Isner.
The start of the final set was a tense affair, with both players hungry to gain an edge.
It was Lopez who eventually got the upper hand, pinning Isner to one game and taking the set 6-1.