The Honda Gresini rider posted a best time of one minute 22.225 seconds, over half a second quicker than his time in the opening practice session, in which the Italian also went quickest.
The second session was run in warmer and less windy conditions than the opener, which was marred by five separate accidents involving some of the sports biggest names. Valentino Rossi, Casey Stoner, Dani Pedrosa, Cal Crutchlow and Toni Elias suffered falls, but all escaped serious injury.
Simoncelli's second-session benchmark was just 0.095s in front of defending world champion Jorge Lorenzo (Yamaha), while Pedrosa, winner at the Sachsenring a year ago, took a strong third in just his second event back since missing three races with a broken collarbone.
The Spaniard finished just ahead of his Repsol Honda team-mates Stoner, the current championship leader, and Andrea Dovizioso, who were fourth and fifth respectively.
Nicky Hayden was the quickest of the Ducati riders in sixth, ahead of fellow American Ben Spies on the second factory Yamaha.
Pramac Racing's Randy de Puniet, Alvaro Bautista (Rizla Suzuki) and Karel Abraham (Cardion AB Motoracing) completed the top 10.
Rossi, who had to be checked over at the medical centre following his morning shunt, endured another trying session as he could manage only 12th fastest before his involvement was curtailed by a late electrical issue.
The Italian finished just behind the struggling Tech 3 Yamaha of Colin Edwards, whose British team-mate Crutchlow was down in 14th.