The Spaniard, a seven-time champion in Rome and now on a 17-match clay-court winning streak, also swept Djokovic aside in the semis in Madrid.
Rafael Nadal, enjoying his best season on clay in two years, booked a quarter-final clash against Austria's Dominic Thiem, whom he beat in the Madrid Masters final last week, after an "aggressive" 6-3, 6-4 win over American Jack Sock, seeded 13th.
Djokovic, a four-time champion in Rome, will meet either Pablo Carreno Busta or Roberto Bautista Agut next.
However, he regained his composure and found a way through and will now face either Kei Nishikori or Juan Martin del Potro in the quarter-finals, with several high-profile stars already into the last-eight.
Speaking to ATP's website, Ferrer, who turned pro in 2002, said: "The number indicates that I have been a very consistent player over many years, and many matches. But I ll keep fighting".
The Swiss was broken just once across the two sets but could not make inroads into the powerful serve of his towering opponent, saving match points in vain late in the second before bowing out.
"It s coming at the right time, we re getting closer to Roland Garros". All the players are looking to raise their game for Paris.
"I went out there with the belief that if I played well and executed my game plan, I could walk off that court with a win".
Isner next faces another big server in sixth-seeded Marin Cilic, who dismissed ninth-seeded David Goffin 6-3, 6-4.
The eighth-seeded Austrian was forced to save three match points before battling to a 3-6 6-3 7-6 (9/7) win over another American, Sam Querrey.
Home favorite Fabio Fognini, who saw off top-seeded Andy Murray on Tuesday, lost 6-3, 6-3 to Alexander Zverev, who will play fifth-seeded Milos Raonic in the quarterfinals after the Canadian beat Tomas Berdych 6-3, 6-2.
Djokovic recently broke off his association with his coaching staff, playing in Madrid accompanied on the bench by his brother, Marko, and he said on Monday that he has not yet decided who will be his next coach.
Russia's Svetlana Kuznetsova, the seventh seed, won't be going so far after she exited following a 2-6, 7-5, 6-4 defeat to Australian qualifier Daria Gavrilova.