Rosol wrote his name into tennis folklore in 2012 by blasting past Nadal in the second round at the All England Club and Murray knew exactly what he would face in their first clash.
The fifth seed, who had a first-round bye, found himself a set and break down on Stadium 1 at Indian Wells Tennis Garden but fought back to win 4-6, 6-3, 6-2, in an hour and 46 minutes.
There was little sign of the twists and turns to come as the first 20 points were all won by the server, Murray finally breaking the sequence in the sixth game.
But it was Rosol who broke serve, correctly challenging what Murray thought was an ace on break point and then thumping a forehand winner. The Czech has one of the most powerful games on the tour and, as he showed against Nadal, can be a threat to anyone when it is working.
It was hit and miss in the early stages and Murray won four points in a row from 40-15 to hit straight back, only for Rosol to break again when an attempted Murray pass bounced off the top of the net and wide. That left the world No 47 serving for the set.
He was lucky to escape a break point when he mis-hit a smash but when he did connect properly there was little Murray could do and Rosol clinched it with another searing forehand.
The Wimbledon champion looked in serious trouble when Rosol played a terrific game to break at the start of the second, but a fifth break in six games followed before Murray finally held.
It was a key moment, and the momentum swung further towards Murray when he broke again to lead 4-2.
Rosol applied pressure with his opponent serving for the set but one amazing scrambling lob helped Murray take it.
The Czech was being forced to go for ever more outrageous winners, and Murray stamped his authority right at the start of the third set.
There had been little to get the crowd excited but a forehand pass on the run from Murray certainly did as he broke for 4-1 on his way to a third-round meeting with either Pablo Andujar or Jiri Vesely.
Murray had earlier been involved in a thrilling doubles clash when he teamed up with Jonny Marray against Gael Monfils and Juan Monaco in front of packed crowds.
After fans queued around the grounds to watch Roger Federer and Stanislas Wawrinka play together, taking on sixth seeds Rohan Bopanna and Aisam ul-Haq Qureshi and winning 6-2, 6-7 (4/7), 10-6, it was standing room only for Murray and Marray's first competitive match together.
Sheffield-born Marray, ranked 43 in the world in doubles, needed to be partnered by a higher-ranked player in order to compete at Indian Wells, leading to the new partnership between the two Wimbledon champions, Marray having won the men's doubles with Frederik Nielsen in 2012.
What always looked like a crowd pleaser of a match did not disappoint. The British duo took the opening set before Monfils and Monaco levelled but it was in the deciding set that the match really came alive. Having led 6-3, Murray and Marray were pegged back to 8-8 but they took their second match point to win 6-4, 4-6, 11-9, after a rally that left Monfils on the floor as he tried in vain to keep the match alive.