Kyrgios and Kokkinakis - doubles partners, great mates and one-time Australian Open junior singles final sparring partners - will duel immediately after an emotion-charged Serena Williams potentially plays the last match of her grand career.

Turning 41 next month, Williams earlier this month declared the US Open would likely serve as her farewell after more than two decades of dominating women's tennis.

The record-setting former world No.1 and 23-times grand slam champion has been duly afforded top billing on Monday night, with Williams opening the evening action on Arthur Ashe Stadium against Montenegro's Danka Kovinic.

Kyrgios and Kokkinakis will follow in prime time in the US, hitting world tennis's biggest stage under New York's bright lights around 9pm (11am Tuesday AEST).

"It will be pretty nuts," Kokkinakis told AAP after a practice session at Flushing Meadows on Friday.

"It's crazy to just look at the court and see how big it is. It's a different feeling, that's for sure."

Almost a decade after Kyrgios trumped Kokkinakis in the 2013 Australian Open boys' final in Melbourne, the Special Ks will be clashing for the first time in the pro ranks.

"It's a huge match," Aussie No.1 Alex de Minaur told AAP.

"As a passionate fan of tennis, I can't see how that can't be a great match - an Aussie clash on one of the biggest stages.

"I'm sure they both would have rather played different opponents but, as a spectator, it will be lots of fun to watch."

Kokkinakis said he could barely believe the must-see first-round match-up materialised at Thursday's draw, which ironically took place in a low-key, officials-only affair on Ashe.

He said he and Kyrgios were practising next to each other when news filtered through.

"It was pretty nuts. I got tweeted at and thought that's got to be wrong. It's less than one per cent chance of drawing each other," Kokkinakis said.

"So it's pretty crazy how it turned out.

"It's kind of surprising it hasn't happened before to be honest. It's a bit weird but we'll go out and try and enjoy ourselves and have fun."

Win or lose, Kyrgios and Kokkinakis will return to Flushing Meadows to team up once again in the doubles, chasing a fourth title of an-already triumphant season together.

The pair are sitting sixth in the rankings race to the ATP Finals in London, which features the top eight teams of 2022, after adding titles in Atlanta and Washington to their stirring run to Australian Open doubles glory in January.

The Kyrgios-Kokkinakis cracker also completes a bumper program of Australians in action on day one of the season's final grand slam.

Aussie No.1s de Minaur and Ajla Tomljanovic, plus Daria Saville, Jordan Thompson and John Millman are also in action.

De Minaur opens against Serb Filip Krajinovic, Thompson plays Italy's Lorenzo Sonego and Millman faces American wildcard Emilio Nava.

Tomljanovic starts against Czech Karolina Muchova and Saville takes on Elena-Gabriela Ruse fresh from reaching this week's final in Quebec.

Fellow Australians Jaimee Fourlis, Rinky Hijikata against the great Rafael Nadal, Jason Kubler, Alexei Popyrin, James Duckworth and Chris O'Connell all open their tournaments on day two.

AUSSIES IN ACTION ON DAY ONE OF THE US OPEN AT FLUSHING MEADOWS (PREFIX DENOTES SEEDING):

Men's singles, first round

18-Alex de Minaur v Filip Krajinovic (SRB)

23-Nick Kyrgios v Thanasi Kokkinakis

Jordan Thompson v Lorenzo Sonego (ITA)

John Millman v Emilio Nava (USA)

Women's singles, first round

Ajla Tomljanovic v Karolina Muchova (CZE)

Daria Saville v Elena-Gabriela Ruse (ROM)

Australian Associated Press