Melzer won 6-3, 7-6 (8-6) and will face Radek Stepanek, a former runner-up in this event. Stepanek, the third seed, ousted Sam Querrey 7-6 (7-5), 6-0.
Querrey won in Memphis two years ago when he defeated Isner in the final.
Milos Raonic and Benjamin Becker also advanced to the semifinals.
Raonic fought off Olivier Rochus 6-3, 7-6 (7-3) and Becker outlasted Lukasz Kubot 7-5, 7-6 (7-5). Becker fell behind 4-0 in the first set and then overcame a 4-2 deficit in the second-set tiebreak.
Raonic reached the final here last year before losing to Andy Roddick, who came into this year's event as the No. 2 seed and did not make it out of the first round.
Swim Week Miami Beach 2014 [PHOTOS]