The Spaniard, who has also won the last six German GPs, took his Honda round in 1min 20.347sec which was 0.287sec quicker than the Yamaha of Fabio Quartararo.
The 20-year-old Frenchman, who took pole in the last race in Assen. struggled with his Yamaha which developed steering problems, causing serious pain in his right shoulder.
There were problems also for Andrea Dovizioso (Ducati) and Valentino Rossi (Yamaha) who failed to get direct entry into the second round of qualifying after missing out on the top 10.
They will instead have to take part in Q1 and hope to progress from there.
Qualification begins at 1235 GMT on Saturday.
Combined free practice times
1. Marc Marquez (ESP/Honda) 1:20.347
2. Fabio Quartararo (FRA/Yamaha) at 0.168
3. Maverick Vinales (ESP/Yamaha) 0.287
4. Cal Crutchlow (GBR/Honda) 0.306
5. Alex Rins (ESP/Suzuki) 0.332
6. Franco Morbidelli (ITA/Yamaha) 0.486
7. Danilo Petrucci (ITA/Ducati) 0.520
8. Jack Miller (AUS/Ducati) 0.544
9. Joan Mir (ESP/Suzuki) 0.639
10. Pol Espargaro (ESP/KTM) 0.672