Defending champion Roger Federer defeated Andre Agassi in the final, 6–3, 2–6, 7–6(7–1), 6–1 to win the men's singles tennis title at the 2005 US Open. It was his second US Open title and sixth major title overall. This was Agassi's last appearance in a major final.
This was the first US Open in which future champions Novak Djokovic, Andy Murray and Stan Wawrinka competed in the main draw. Noteworthy in this tournament was a strong performance by American men, despite 2003 champion and former world No. 1 Andy Roddick losing in the first round. In addition to two-time US Open champion Agassi, wildcard James Blake reached the quarterfinals, upsetting world No. 2 Rafael Nadal in the third round before losing to Agassi. Robby Ginepri, whose run was enhanced by Roddick's early defeat, reached the semifinals and also lost to Agassi.
This tournament marked the last major appearance for former world No. 6 and French Open champion Albert Costa.
The seeded players are listed below. Roger Federer is the champion; others show the round in which they were eliminated.
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Roger Federer (champion)
Rafael Nadal (third round).svg/1280px-Flag_of_Australia_(converted).svg.png){kind=small}
Lleyton Hewitt (semifinals)
Andy Roddick (first round)
Marat Safin (withdrew) Nikolay Davydenko (second round) Andre Agassi (final)
Guillermo Coria (quarterfinals) Gastón Gaudio (first round) Mariano Puerta (second round) David Nalbandian (quarterfinals)
Tim Henman (first round)
Richard Gasquet (fourth round)
Thomas Johansson (second round)
Dominik Hrbatý (fourth round)
Radek Štěpánek (second round) David Ferrer (third round)
Ivan Ljubičić (third round) Tommy Robredo (fourth round) Juan Carlos Ferrero (first round)
Fernando González (third round) Mario Ančić (second round) Jiří Novák (second round, withdrew) Mikhail Youzhny (third round) Taylor Dent (third round) Feliciano López (second round).svg/1280px-Flag_of_Belgium_(civil).svg.png){kind=small}
Olivier Rochus (third round) Greg Rusedski (first round)
Tommy Haas (third round)
Max Mirnyi (third round) Carlos Moyà (second round) Tomáš Berdych (third round)