Just weeks after a record 10th French Open title, the 31-year-old Spaniard lost 6-3, 6-4, 3-6, 4-6 and 15-13.
Despite fighting back from two sets down, Rafa says: “I had my chances, and he had some.”
The 34-year-old Muller will now face Marin Cilic in the quarterfinals.
The Luxembourger is joined by defending champion Andy Murray and Sam Querrey, who face one another.
Eight-time winner Roger Federer takes on last year’s losing finalist Milos Raonic.
Meanwhile, second seed Novak Djokovic yesterday completed the last-eight line-up after beating Adrian Mannarino in straight sets to set up a meeting with Czech Tomas Berdych.
The three-time champion then went on to complain about a “hole” on Centre Court.
The Serbian explains: “During the match I mentioned that there is a hole in the middle of the court, middle of the service line and he [the match official] asked me to show him and I did. He was not very pleased to see that.”
The Serb is not the first player at this year’s tournament to comment negatively about the quality of the courts but said he understood the difficult job facing the ground staff.
The 30-year-old 12-time GrandSlam winner adds: “The courts honestly are not that great this year and many players feel the same. It is what it is, the weather also affects the grass.”