Former US Open champion Murray will take on the Greek star at Flushing Meadows, with top seed Novak Djokovic taking on a qualifier in his bid for a clean sweep of the majors in 2021.
The New York tournament will take place without a host of injured stars, with both Williams sisters, Roger Federer, Rafael Nadal and Dominic Thiem all missing.
Serena Williams has pulled out with a hamstring injury, while older sister Venus has missed out due a long-standing leg problem.
Five-time champion Federer remains sidelined with knee surgery, while Nadal has a foot complaint and Thiem a wrist problem.
Women's world number one Ashleigh Barty takes on Vera Zvonareva, while top-ranked Brit Johanna Konta will face Kristina Mladenovic.
Defending women's champion Naomi Osaka will bid for a third title in four years when the competition starts on Monday.
The Japanese star and third seed has been drawn in the other half of the draw from world number one Barty, and will begin her title defence against the Czech Republic's Marie Bouzkova.
The 26th men's seed Cameron Norrie has been paired with Spanish teenager Carlos Alcaraz, with top-ranked British male star Dan Evans takes on Brazilian Thiago Monteiro.
Heather Watson will take on Slovenia's Kaja Juvan, while Americans Sloane Stephens and Madison Keys meet in the first round.
Nick Kyrgios and Roberto Bautista Agut make another tasty first-round tie.