Sixteen years after they first met in a junior competition in France, the pair are set to lock horns for the 21st time as professionals, their sixth grand slam clash but at the earliest stage of the lot.
World number one Novak Djokovic will enter the match as the favourite, having reached the last eight without dropping a set, while Murray looked back on form in beating Jo-Wilfried Tsonga to make the quarter-finals.
Djokovic leads Murray 12-8 over their careers - but tellingly, has won four of his last five encounters. In addition, all of those wins were on hard courts - the sole win for Murray during those clashes being the 2013 Wimbledon final. Given Murray's shaky season and injury-interrupted last 12 months, Djokovic is unsurprisingly a 2-7 odds-on favourite, with Murray 11-4 to make the semi-finals.
Yet Murray has the advantage of having beaten Djokovic in their only previous encounter in New York: the 2012 US Open final, which Murray took in five sets.
Despite his superb form, the Serb is well aware of how tough a match he faces.
"I think Andy also performs his best in the grand slams," said Djokovic.
"In the big matches, as the tournament progresses, he's still fit. He still plays very high quality tennis. That's what I expect him to do."
Andy Murray reacts after defeating Jo-Wilfried Tsonga
The pair are the only two men to have reached at least the quarter-finals of all four grand slams this year.
Murray said there were unlikely to be many surprises between the two but in his column with the New York Times, he said the weather could be significant, a reference, perhaps, to the 2012 final when he coped better with the wind than Djokovic.
"You can't just have the same tactics every single time you play him," said Murray.
"There needs to be some adjustments depending on the surface and the conditions. We'll see what those are Wednesday."
Japan's Kei Nishikori will be hoping to rebound from his marathon win in the previous round, which equalled the latest ever US Open finish of 2:26 a.m. ET, when he takes on third seed Stan Wawrinka of Switzerland.
Women's top seed Serena Williams plays Italy's 11th seed Flavia Pennetta for a place in the semi-finals while Victoria Azarenka, the runner-up in each of the past two years, faces Russia's Ekaterina Makarova.
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