The Pitt - the year's top nominee with 25 and the reigning best drama winner for its first season - also won on Sunday for its prosthetic makeup and its casting.
Another top nominee, Apple TV's first-year horror comedy Widow's Bay, brought in four trophies of its own, including wins for production design and sound.
Harden, who won for playing Louie Cloverfield, the emergency room's constant presence and constantly struggling alcoholic on The Pitt, wept when his name was called.
"I am just on cloud 25," he said backstage at the Peacock Theater in Los Angeles.
"I'm not saying it's a complete surprise because The Pitt is such a powerful show to come from, but just to get it in your hands is unreal."
Harden's first speaking role was in the 1975 Robert Redford-Faye Dunaway thriller Three Days of the Condor but has acted for decades without awards recognition.
The Pitt dominated this year's drama acting nominations for its second season.
Harden's category included fellow Pitt guest star Jeff Kober. Three women from the show were up for best guest actress in a drama, but all lost out to Shailene Woodley for her role on Paradise.
Woodley said backstage that she was a fan of the dystopian Hulu series during its first season, and loved getting to play a survivor who holes up for years alone in Elvis Presley's Graceland in Memphis to open its second season.
"The whole Paradise journey from beginning to end is just a gift that continues to give," Woodley said.
It was her first Emmy win. She was previously nominated for her role on Big Little Lies.
Spider Noir, which was cancelled after one season last week by Amazon Prime Video, won four Emmys including visual effects and stunts.
The Television Academy hands out well over 100 primetime Emmys, and most of them are being presented this weekend in a pair of ceremonies.
They were previously known as the Creative Arts Emmys but have now been rebranded as simply the first two nights of the 78th Emmy Awards.
The two nights will be edited together to air September 12 on FXX and stream on Hulu the following day. The primetime September 14 ceremony, also at the Peacock Theater and hosted by Mariska Hargitay, will air live on NBC.
Hargitay was among this weekend's winners, getting two Emmys for the documentary she directed about her mother, Jayne Mansfield, My Mom Jayne, to go with the best actress in a drama Emmy she won in 2006 for Law & Order: Special Victims Unit.
Bad Bunny won his first career Emmy Award for his Super Bowl halftime show, which took seven trophies at the first of the weekend's ceremonies on Saturday.
Two other Apple TV Emmy rookies also won multiple trophies along with Widow's Bay.
Pluribus, the one-woman-against-the-hivemind drama from Breaking Bad creator Vince Gilligan that could challenge The Pitt in the top categories, won for its editing, production design and sound mixing. Margo's Got Money Troubles also won three craft awards.
Netflix's Beef was thriving in the limited series categories, with three wins including trophies for costumes and sound.
Rob Reiner, who was killed along with his wife Michele Singer Reiner in December, could win a posthumous Emmy later Sunday. He was nominated for guest actor in a comedy for The Bear, about 50 years after winning two Emmy Awards for his acting on All in the Family.
Five-time Emmy winner Michael J Fox is also nominated in the same category for playing a patient on "Shrinking" who has Parkinson's disease, which the actor was diagnosed with in the 1990s.
The evening's star power will be increased by the academy moving five categories from the September 14 telecast to Sunday. They include best supporting actor and actress in a limited series, with nominees such as Jason Bateman, Charles Melton, Laurie Metcalf and Dakota Fanning.
