Sinner's withdrawal has added to the intrigue around the final Grand Slam of the year, and several players will now have their eyes on the prize, well aware that this could be as good an opportunity as ever to get their hands on a Slam title.
So ahead of the tournament, we take a deeper dive into the men's draw, analysing who could make it out of each quarter before making a final prediction.
First quarter
Seeds: Alexander Zverev (1), Alex de Minaur (6), Rafa Jodar (12), Lorenzo Musetti (13), Casper Ruud (19), Luciano Darderi (21), Alejandro Tabilo (25), Zizou Bergs (31)
The top half of the draw is a lot less stacked than the bottom, and top seed Zverev will be pleased to have ended up in this section. The Roland Garros champion shouldn't fear anyone up until the quarter-finals, but the rising Jodar would be a serious test.
De Minaur comes in with no form whatsoever, and Musetti has struggled with injury issues. As a result, there are two clear standouts in this quarter.
Prediction: Zverev to beat Jodar in the quarter-finals
Zverev hasn't been playing anywhere near his best during the North American hard-court swing since his incredible summer form, which saw him win in Paris and reach the Wimbledon final. If he continues to be off his game, Jodar - who has had an astonishing 12 months to climb to 13th in the world rankings - could take him out.
However, despite his struggles at this tournament in recent years, the German is generally a tough man to beat at Slams, and over five sets, he might be too strong for his 19-year-old opponent.
Second quarter
Seeds: Felix Auger-Aliassime (3), Flavio Cobolli (5), Taylor Fritz (9), Learner Tien (14), Jakub Mensik (17), Francisco Cerundolo (24), Alexander Blockx (28), Ignacio Buse (32)
A really open quarter in the draw; several players will be eyeing a run to the semi-finals in this part of the bracket. Third seed Auger-Aliassime has reached the last four twice in New York, including in 2025, and Cobolli reached his maiden Slam final in Paris this year.
Additionally, home favourite Fritz has reached the US Open final before, while Tien and Mensik are two exciting young talents.
Prediction: Fritz to beat Auger-Aliassime in the quarter-finals
As long as his tendinitis doesn't flare up, Fritz's big-hitting, big-serving game in front of a vocal home support should make him the person to beat in this section. He could be too strong for his rivals, and should overpower Cobolli and Auger-Aliassime on his way back to the semis.
Third quarter
Seeds: Novak Djokovic (4), Daniil Medvedev (7), Frances Tiafoe (11), Brandon Nakashima (16), Valentin Vacherot (22), Andrey Rublev (23), Arthur Rinderknech (26), Tomas Martin Etcheverry (27)
Now we are onto the half packed with dangerous names and in-form players. Here, Djokovic lurks, as he begins another run at a record-breaking 25th Grand Slam title. The legendary Serb hasn't looked fit, lacks form, yet can we really rule him out? He has consistently upped his level at the majors even though he is nearly 40, and has regularly reached the semi-finals.
Medvedev is hopelessly out of form and even contemplated taking up pickleball during his defeat at Winston-Salem earlier this week. But Nakashima is playing the tennis of his career, and Tiafoe just reached the Cincinnati final. The latter loves playing at home too, reaching the semi-finals in 2024.
Prediction: Tiafoe to beat Djokovic in the quarter-finals
Backing against Djokovic might be completely foolish, but he looked unconvincing and struggled with his fitness when he lost his first match in Cincinnati. Tiafoe seemed to be full of confidence at that event, on the other hand, and may have what it takes to dump Djokovic out.
Fourth quarter
Seeds: Carlos Alcaraz (2), Ben Shelton (8), Arthur Fils (10), Alexander Bublik (15), Jiri Lehecka (18), Tommy Paul (20), Cameron Norrie (29), Matteo Arnaldi (30)
This quarter is probably hardest to pick purely because of Alcaraz. The defending champion returns to singles action for the first time since picking up a wrist injury back in April, so we just don't know what to expect. If he is anywhere near his best, he will win the US Open. But in all likelihood, he will be really rusty and won't be able to find his top level during the tournament. His first-round match is a tricky test against Roman Safiullin.
He has also landed in a section with two recent Masters 1000 champions. Shelton won the title in Montreal while Fils reigned victorious in Cincinnati. He couldn't have asked for harder potential last-eight opponents.
Prediction: Shelton to beat Alcaraz in the quarter-finals
It is really difficult to envision Alcaraz being fully fit and firing, so while he could get through a few rounds, overcoming Shelton or Fils feels like a bit of a stretch. The former looked absolutely superb in Canada, and thrives under the New York lights. It could be the American's moment.
Semi-final and final predictions
Semi-final 1: Alexander Zverev to beat Taylor Fritz
Semi-final 2: Ben Shelton to beat Frances Tiafoe
Final: Alexander Zverev to beat Ben Shelton
Both of these potential semi-finals would be ultra-competitive. Fritz leads the head-to-head with Zverev 10-6, and won seven meetings in a row between the pair before the German beat him at Wimbledon.
If Zverev has reached the semi-finals, logic suggests he would be close to his best, and that may be enough to overcome the American once more.
Meanwhile, the other semi-final would certainly be a broadcaster's delight in the USA, and it would make for absolute box-office viewing. In addition, neither player has reached a Grand Slam final before, so there would be so much on the line.
Shelton has a higher ceiling though, and with tonnes of momentum and confidence, that should help him into the final.
Zverev and Shelton have played each other five times, and the former has won every single time. He adores playing left-handers, holding a 42-1 record against them since Roland Garros in 2023. His backhand cross-court is so imperious that it often negates the advantage lefties have.
That has to be a factor, alongside the fact that Zverev has far more experience on the big stage. The pressure has also been relieved from him after he won his maiden Slam earlier this year, so he should be in a better position regarding nerves.
If Zverev were to win it, he'd have captured two of the last three majors, reaching three consecutive finals in the process. Imagine telling people that after the Australian Open, when Sinner and Alcaraz had won nine Grand Slams in a row.