Muller's 2m00.749s from the opening session stood as the fastest until midway through the second, when he was usurped by team-mates Ma Qing Hua, Sebastien Loeb, and then finally Lopez.
The world champion eclipsed Loeb's time by 0.274s but narrowly missed out on breaking the two-minute mark, lapping in 2m00.155s.
Norbert Michelisz was third, and fastest of the Hondas, in the first session, but Argentine Super TC2000 champion Nestor Girolami took that honour in FP2, using fresh tyres to come within thousandths of a second of displacing Loeb.
Tiago Monteiro was the quickest of the works Honda drivers, fifth overall and half a second down on Lopez, while the best Muller could summon in FP2 left him sixth, 0.592s off his team-mate.
Lada's Vestas have struggled for pace around Vila Real thus far, and the strain of extracting performance from the car started to show as both Jaap van Lagen and Nicky Catsburg fell foul of the stewards.
Van Lagen, who had already been cautioned over respecting track limits in first practice, had two flying laps scratched for repeat offences at the Turn 19 chicane and was then black-flagged.
Catsburg was shown the black-and-white flag but kept his nose clean thereafter.
Rob Huff was the fastest of the Lada trio in both sessions, and seventh quickest in FP2, but half a second slower than sixth-placed Muller and 1.184s adrift of Lopez.
Tom Coronel, who was also cautioned over track limits, was the quickest of the Chevrolet runners in FP2, ninth overall, neatly matching Campos Chevrolet driver Hugo Valente's position in the pecking order in FP1.
The first practice session was largely incident-free until the final minute.
Both Huff and Girolami had harmless slides, and Coronel had a wheelarch liner work loose, but the session had to be stopped with just over a minute left on the clock when Gabriele Tarquini slammed into the back of Tom Chilton's Chevrolet at Turn 6.
A furious Tarquini accused Chilton, who had been on an out-lap, of dawdling on the racing line, but the stewards took a different view and handed the Italian a reprimand.
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