The Serb polished off his Russian opponent in two hours and 34 minutes on Arthur Ashe Stadium to set up a last four meeting with Stanislas Wawrinka, who earlier stunned defending champion Andy Murray.
"I've been always trying to play my best tennis in the Grand Slams," said Djokovic, who has now reached the semi-finals at 14 successive Majors.
"I had a tough hard court season coming into the US Open but I'm really working on my game. I'm going to try to play my best in every match."
At two sets up, Djokovic looked to be forging an even quicker path to the last four but Youzhny burst into life to become the first player to take a set off the world number one at Flushing Meadows this year.
The New York crowd swung behind the underdog but Djokovic recovered momentum by breaking the Russian's opening service game of the fourth set.
With entrepreneur Richard Branson cheering him on from his supporters' box, Djokovic broke again in the fourth and sixth games to put the issue beyond doubt.
"After I lost the third set I definitely tried to regroup and focus on every point individually," said the 26-year-old, who hit 32 winners and an unusually high 45 unforced errors.
"It suddenly changed. For some reason I allowed him to come back into the match, started to push the ball, being more passive and allowing him to step into the court.
"It was important to get the early break in the fourth. I really felt a big relief and just went for my shots and played great."
The clash between Djokovic and ninth seeded Swiss Wawrinka will be their first since an epic battle at this year's Australian Open, which the Serbian won 12-10 in the fifth set before going on to win the title.
"That was played on a very, very high level," Djokovic said.
"In the past we all knew (Stan) had the quality to play that well, but not on a consistent basis. I think he has worked on his movement a lot, and some variety of shots in his game.
"He's a very complete player. He's had one of the best seasons of his life. Today he won in straight sets against the defending champion on Arthur Ashe. That's quite impressive."
Murray complained about an emotional letdown from his Wimbledon victory and Djokovic said he understood.
"It's never easy after you win a Grand Slam to motivate yourself again to play smaller tournaments," the six-times Grand Slam champion said.
"And then prepare yourself again to be mentally, physically and emotionally 100 per cent committed to another Grand Slam that is basically just a month and a half after the biggest win in his career, which is Wimbledon.
"I have been in this particular situation. I know how it feels. But this is tennis. In order to be in the mix for number one in the world or a contender for a Major title, you have to be giving everything that you have."
- Sports & Recreation
- Stanislas Wawrinka
- Arthur Ashe Stadium