Novak Djokovic, the dominant player for the past three seasons, will be making his sixth consecutive appearance in the semis, defending the title he won last year.
Olympic champion Andy Murray is through to the last four for the third time in five years while Spain's David Ferrer is making his second semi-final appearance in New York.
Only Czech Tomas Berdych, who upset Federer in the quarter-finals, is a newcomer to the US Open semi-finals but he is no stranger to the big stage, having made the Wimbledon final two years ago.
The last time Federer and Nadal were both missing from the semi-finals of a Grand Slam was at the French Open in 2004. The last time neither man made the semis in New York was in 2003.
"You have Murray, Berdych, Ferrer, myself, we're all top-10 players," said Djokovic. "This is tennis. Everybody is trying and has the motivation to perform at their best.
"I still feel that we are having a really good tournament."
With Federer eliminated and the injured Nadal not even making the trip to the Big Apple, Djokovic and Murray are the clear favourites to reach the final.
Djokovic has already won five Grand Slam titles, including each of the last three played on hard courts, and is unfazed by the added burden of defending his title, reaching the semi-finals without dropping a single set.
"I have learned over the years how to deal with it and how to cope with the pressure and get better on the court, off the court, understand the game better," said the Serbian.
"So right now, I'm just trying to focus on every game individually, but it definitely has a special feeling about it coming as a defending champion. It's unique and I love it."
Djokovic's opponent is Ferrer, who was elevated to fourth seed after the withdrawal of his Davis Cup team mate Nadal.
Although the 30-year-old has never made a Grand Slam final, he is through to his fourth career semi and has been one of the leading players on the tour this year, winning five titles and making at least the quarter-finals of all four major.
A dogged player who never seems to tire, he is also regarded as one of the toughest players to beat and won an epic fifth set tiebreaker against Janko Tipsarevic to make the semis.
"Of course, this season was the best of all my career. I don't know why." he said. "I am playing with very confidence. I am older, you know, I don't have too much pressure."
For Murray, the absence of Federer and Nadal presents him with his best chance to end Britain's 76-year wait for a Grand Slam men's champion.
The Scotsman has played in four Grand Slam finals, including the US Open in 2008 and Wimbledon in July, but lost the lot.
Questions have been raised about his ability to handle the pressure on the biggest occasions but he silenced the doubters when he won the gold medal at the London Olympics.
"You never know exactly what's going to happen ... I would hope that, going into the match on Saturday, win or lose, I'll be in a good place mentally," Murray said. "I'll fight from the first point to the last. If I do that, I'll give myself a shot."
Berdych presents a real challenge to Murray. The Czech is one of the hardest hitters in the game and brimming with confidence after his brilliant performance to beat Federer.
"If my game is well and I'm able to play my game, then I have a quite dangerous game to beat anyone," he said.
- Novak Djokovic
- Tomas Berdych