Frenchman Simon was ousted by Marcos Baghdatis 6-3 6-4 in the first of the day's quarter-finals at the Queensland Tennis Centre.
Cypriot Baghdatis won 78 per cent of his first serves and broke the French third seed three times on his way to what was a comfortable victory.
Baghdatis now plays Grigor Dimitrov for a place in the final, after the Bulgarian toppled seventh seed Juergen Melzer 6-3 6-2 in another upset.
Dimitrov fired down 17 aces, winning 84 per cent of his first serves and taking all four of the break points he had in a match that lasted just under an hour.
Alexandr Dolgopolov was another seed to fall as the fourth seeded Ukrainian lost 6-4 7-6(3) to Kei Nishikori, the fifth seed.
Japan's Nishikori will play the winner of top seed and defending champion Andy Murray's quarter-final with Denis Istomin, to be played later in the day.
ATP Brisbane results
Grigor Dimitrov (Bulgaria) beat 7-Juergen Melzer (Austria) 6-3 6-2
5-Kei Nishikori (Japan) beat 4-Alexandr Dolgopolov (Ukraine) 6-4 7-6(3)
Marcos Baghdatis (Cyprus) beat 3-Gilles Simon (France) 6-3 6-4