Melbourne Renegades captain Aaron Finch will also make his Australian ODI debut, along with fringe Test batting candidate Usman Khawaja.
Finch and Hughes will open the batting for Australia, while Khawaja is set to slot in at No.3.
Big fast bowler Ben Cutting and all-rounder Steve Smith both missed out on selection after being named in the initial 13-man squad.
Tasmanian George Bailey will captain the side and delcared there was a real air of excitement in the group.
Australian team for First ODI against Sri Lanka:
George Bailey (c) TAS
Xavier Doherty TAS
Aaron Finch VIC
Brad Haddin NSW
Phillip Hughes SA
David Hussey VIC
Mitchell Johnson WA
Usman Khawaja QLD
Glenn Maxwell VIC
Clint McKay VIC
Mitchell Starc NSW
Bailey said it was exciting to have three debutants to open the Australian innings.
"Certainly all three, I think, have earned their place, their domestic records are outstanding," Bailey told a press conference in Melbourne on Thursday.
"I think the couple of Twenty20 games that Finchy's played, he's played really well, man-of-the-match in one of those.
"And Hughesy's obviously looked really at home in the Test side since he's been back there.
"So I'm looking forward to seeing how they go."
Khawaja was called into the Australian Test squad as cover for Clarke, but never made it into the starting XI.
Finch, who has led the Renegades in a dominant Big Bash rampage this summer, will now sweat on whether or not Cricket Australia will be willing to release him for his domestic franchise duties.
Australia's side has come under heavy fire after selectors opted to rest key stars from the first limited-overs hit-out, including Test captain Michael Clarke, hard-hitting opener David Warner and 'keeper Matthew Wade.
Recently-retired batting great Mike Hussey was left out of the one-day squad altogether, after selectors declared they planned on focusing on the future.
Bailey said the side's selection points to planning for the upcoming series against India and then the highly-anticipated Ashes mid-year.
"I think there's no doubt that there's one eye on different tours coming up this year and also on the World Cup in 2015," Bailey explained.
"And I think if these guys perform really well, what you could see is the core of the Australian side, come 2015."