Juan Martin del Potro made sure of that Wednesday night, when the tournament's No. 24 seed stunned Federer 7-5, 3-6, 7-6(8), 6-4 to move into the semifinals and set up a date with the top-ranked Nadal.
That showdown will comprise half of Friday's bill on the men's side, which also boasts a clash between No. 28 Kevin Anderson and No. 12 Pablo Carreno Busta—each of whom is making his first appearance in a Grand Slam semifinal.
Date: Friday, September 8
Coverage: Begins at 4 p.m. ET
Live Stream: WatchESPN
No, Nadal and Federer won't be able to share the court. But a matchup between the world No. 1 and a surging del Potro is a fine consolation.
On one hand, there's Nadal, who has ripped off five straight wins over unseeded opponents, including straight-set efforts in his last two matches.
On the other, there's del Potro, who has dispatched No. 11 Roberto Bautista Agut, No. 6 Dominic Thiem and Federer in his last three outings.
Based on that grueling schedule, it stands to reason del Potro could be running on fumes come Friday.
But as the New York Times' Christopher Clarey noted, del Potro is looking dangerous as ever after he registered 48 winners against Federer:
Del Potro also has a track record of devising successful game plans against Nadal.
Although the 15-time Grand Slam champion is 8-5 against del Potro lifetime, the Argentine has won two straight, including a semifinal at last summer's Olympics in Rio de Janeiro, Brazil.
The winner of that match will square off against either Anderson or Carreno Busta, who figure to put on quite a show in the other semifinal.
While neither player packs the same name recognition as Nadal or del Potro, they have both made the most of a wide-open draw.
Anderson, the tournament's 28th seed, opened his stay in Flushing, New York, with three consecutive straight-set wins before he needed four sets to dispatch Paolo Lorenzi in the fourth round and Sam Querrey in the quarterfinals.
Carreno Busta, meanwhile, has yet to drop a set at the year's final major.
"Of course I know that I have a good draw here," Carreno Busta said after defeating Diego Schwartzman in the quarters on Tuesday, per ATPWorldTour.com. "But when you have this draw, you have to do your best to take advantage, so I think that is a really good tournament for me. I know that I didn't win matches against top players, Top 10 or Top 20 players, but I am very happy with my tournament."
Looking ahead, Carreno Busta could have his hands full with Anderson.
The South African is 2-0 all-time against Carreno Busta, including a straight-set win last month at the Rogers Cup in Montreal.
Their only other meeting came in 2013 when Anderson made light work of Carreno Busta in Morocco.
On paper, those results aren't encouraging for Carreno Busta.
But after getting a look at Anderson in August, the Spaniard should have a more complete understanding of how to attack his opponent as they each attempt to secure spots in their first Grand Slam final.