The two clash in the fourth round at Flushing Meadows on Tuesday, with the pair having met just once before.
However, the 26-year-old from Uzbekistan is relishing the opportunity to square off against the reigning champion.
"I'm looking forward to it," Istomin told reporters. "I've just played him once, I lost in two sets. But it was a close match. I will try to play the same tactics as I did there and we will see what happens.
"He's a great returner. He returns almost everything. The key is my serve. I will try to serve better than usual. He moves on the court incredibly but I will try to move him more and try to beat him.
"If I win, it will be the biggest match of my life. I'm looking forward to this match. I will try to play my game and concentrate on winning."
Murray advanced to the fourth round after beating Florian Mayer on Sunday.