French Open runner-up Soderling broke 16-time Grand Slam champion Federer's streak of 23 Grand Slam semi-finals in a row with a quarter-final triumph on the Paris red clay over the Swiss superstar who had won their 12 prior matches.
Swedish fifth seed Soderling, who lost the Roland Garros final to top-ranked Rafael Nadal, and world number two Federer each need one more victory to book a rematch on the Flushing Meadows hardcourts after third-round triumphs yesterday.
"Everybody has been telling me since the draw came out I'm playing Roger in the quarters. It's still far ahead," Soderling said.
"It's always difficult to play against Roger and I have played him a lot of times. In any tournament they play, Roger and Rafa will be the favorites, but there are a lot of players who can beat them."
Five-time US Open winner Federer hit 13 aces and 31 winners in brisk winds that tested even his formidable skill to down 109th-ranked Frenchman Paul-Henri Mathieu 6-4, 6-3, 6-3, and reach the last 16.
"The wind was very strong. Tough conditions to play in, especially if you're down in the score," Federer said. "You could tell Mathieu was really struggling after being down. His serve, his returns, everything kind of falls into pieces.
"It's really hard to stay positive when you're down and the wind is the way it is. You have to be careful, maybe not aim at the lines as much. After four games or so, I knew what I could do and what I couldn't."
Soderling beat 48th-ranked Dutchman Thiemo de Bakker 6-2, 6-3, 6-3 in gusty conditions that were remnants from Hurricane Earl's nearby brush a day earlier.
"It was very tough. I was fighting the wind the whole time. During these conditions I played a pretty good match," Soderling said. "It's great to make it to the second week at the US Open. It will be very big next week."
Also advancing to the fourth round was Serbian third seed Djokovic, who eliminated US wildcard James Blake 6-1, 7-6 (7/4), 6-3 to book a date with US 19th seed Mardy Fish.
"It felt like Hurricane Earl came to the center court. It was incredible," Djokovic said. "It was a big mental struggle just to stay on the court and stay focused. If James had won the second set it could have been a different match."
Federer, trying for his seventh US Open final in a row, next faces Austrian 13th seed Jurgen Melzer, whom Federer ousted in this year's fourth round at Wimbledon in their only prior meeting.
Soderling will meet Spanish 21st seed Albert Montanes, who led 6-2, 2-1 when 147th-ranked Japanese qualifier Kei Nishikori retired after only 38 minutes with a groin injury.
"He was not well physically so that was lucky for me," Montanes said. "I realised he was very flat. He was not moving. I tried not to think of that but he was moving quite slowly."
Federer, seeking his 64th career title, had won 40 US Open matches in a row before losing last year's final to now-injured Juan Martin Del Potro.
Federer saved a break point on a service winner in the eighth game and broke on an errant Mathieu backhand in the ninth to win the first set and took the second when Mathieu double faulted away breaks in the third and last games.
"The first set was key," Federer said. "After that I was able to break it back and break his will a little bit."
Federer broke Mathieu in the sixth game of the last set, then saved three breaks points in the final game and held to win in 99 minutes.
Melzer beat Spain's Juan Carlos Ferrero 7-5, 6-3, 6-1 to book a date with Federer.
"I really enjoyed the way I played," Melzer said. "I was really on top of him and really had the momentum going."
Montanes claimed his first spot in the fourth round in 36 Grand Slam trips. He was among nine Spaniards in the third round, the most at any Open-era Slam.
French 17th seed Gael Monfils fired 17 aces and 56 winners to beat Serbia's 44th-ranked Janko Tipsarevic 7-6 (7/4), 6-7 (4/7), 6-2, 6-4.
Monfils booked a fourth-round match with countryman Richard Gasquet, who ousted South African Kevin Anderson 6-4, 7-6 (7/3), 7-5. Monfils and Gasquet each matched their best US Open result by reaching the fourth round.