Valentino Rossi set the tone for a chaotic session when he crashed changing direction at Turn 9 on his maiden outlap, thrown off his Yamaha in a highside.
The cooler morning conditions also caught out Alex Lowes, who crashed at Turn 16 and went to the medical centre reporting foot pain, and Aprilia's Alvaro Bautista, who went down at Turn 14.
Between those two falls, Marquez moved to the top of the order with a 1m48.185s and then 1m47.810s lap.
The latter was the first beneath the 1m48s-barrier of the weekend, and 0.619 seconds faster than the Friday pace set by his Honda team-mate Dani Pedrosa.
Just after Rossi returned to the track, nearly 20 minutes into the session, Lowes' team-mate Pol Espargaro lost the front end of his Tech3 Yamaha at Turn 2.
That sent his bike across pit exit and into the path of Pramac Ducati's Danilo Petrucci - who was leaving the pitlane - and while Petrucci hit Espargaro's bike, both riders avoided injury.
When Espargaro headed back out on his spare bike, he was caught up in another major incident.
Filling in for Jack Miller at Marc VDS Honda, Nicky Hayden crashed at Turn 14 and as marshals and the 2006 world champion tended to his bike, they had to take evasive action.
Behind Hayden on the road, Marquez looked up the inside of Espargaro under braking, but he came unstuck, sending both riders down the road and towards Hayden's Honda.
Espargaro's bike hit Hayden's and his session was over, but the Spaniard wound up 10th in the combined order based on his Friday efforts to book a place in the second phase of qualifying.
Marquez nursed his right shoulder and damaged Honda back to the garage and was able to rejoin the session on his second bike.
With three minutes to go, Marquez was one of only two riders inside the top 10 who had improved on his Friday times, and while he did not trouble that benchmark again, it remained good enough to finish on top.
LCR Honda's Cal Crutchlow went second fastest with three minutes remaining to close the gap to 0.362s, and he improved again after the chequered flag to a 1m48.006s, meaning Marquez's final margin was 0.196s.
By the end of the session, the bulk of the top 10 riders had improved, with Suzuki's Maverick Vinales and Aleix Espargaro third and fifth, split by Yamaha's Jorge Lorenzo.
Pedrosa lapped four tenths slower than his Friday-afternoon pace and was eighth in the session, but sixth on the combined times that determine the Q2 field.
Scott Redding vaulted his way from 16th to seventh overall and a place in Q2 with his final effort, while Ducati's Andrea Dovizioso and Rossi wound up eighth and ninth, ahead of Pol Espargaro.
Standing in for the injured Andrea Iannone, Michele Pirro was 14th on the second Ducati, ahead of Aprilia pair Stefan Bradl and Bautista.