Zverev captured a long-awaited first Grand Slam title at the French Open this year and finished runner-up to world No. 1 Sinner at Wimbledon.
Alcaraz, whose Australian Open title in January made him the youngest man to complete the career Grand Slam, missed both of those tournaments with a right wrist injury that the Spaniard said is fully healed.
But more than four months have elapsed since he last played, and it remains to be seen if he has the requisite fitness to become the first man to win back-to-back US Open titles since Roger Federer won his fifth straight back in 2008.
"I expect him to be maybe a bit rusty the first or second match, but once he gets through that, I think he's going to be a contender for sure here," Zverev said.
A host of players who could challenge the top two seeds includes 39-year-old Novak Djokovic, seeded fourth as he again chases a record-setting 25th Grand Slam singles title.
Djokovic said his early exit amid physical struggles in the Cincinnati Masters had a silver lining, allowing him to "really train and get my body and mind into the right state, prepared for what's coming up."
Like Zverev, Shelton was reluctant to paint Sinner's withdrawal with a knee injury as an automatic boost to his own title hopes.
"I know how much quality that there is in the draw," Shelton said. "I think it would be disrespectful to just think 'Oh, there's no Sinner, it's a massive opportunity."
Shelton pointed to Zverev, the returning Alcaraz and Djokovic, but also to rising talents like France's Arthur Fils, who won his first ATP Masters title in Cincinnati last week.
"All the American guys are pretty dangerous on this surface," added Shelton, who retired from the third round at the US Open last year with a shoulder injury. "I think to kind of discredit the group that is playing high-level tennis right now wouldn't be smart."
Women's world No. 1 Aryna Sabalenka insists no one should count her out as she bids to become just the third woman, after Chris Evert and Serena Williams to win three straight US Open titles.
But since her back-to-back hard-court titles in Indian Wells and Miami the Belarusian star hasn't reached a final, and even if she pulls off the rare treble she could still lose her world top ranking.
Second-ranked Elena Rybakina, who beat Sabalenka for the Australian Open title in January, has been steadily closing in and could secure the top spot with a run to the semifinals regardless of Sabalenka's results.