Apple TV's first season Widow's Bay overcame the final season of previous winner Hacks to earn the comedy prize.
Hacks star Jean Smart won her fifth Emmy for portraying tenacious stand-up comic Deborah Vance, and Matthew Rhys became the first person to win two lead acting honours at the same ceremony, including one for his role as a small-town mayor on Widow's Bay.
Smart's accolade made her the first performer to win the Emmy for best comedy actress for every season of a show's run.
"What a ride this has been!" Smart said on stage after thanking the creators of the HBO Max show.
Julia Louis-Dreyfus, who won best comedy actress for six of the seven seasons of Veep, is the only woman to come close to Smart's milestone.
The Pitt star Noah Wyle said it felt "overwhelming" to land his second straight Emmy for playing Dr "Robby" Robinavitch on the medical drama set in a Pittsburgh trauma centre.
Describing himself as a "Hollywood kid," Wyle told the Emmy audience, "This is the only club I've ever wanted to join. Thank you for accepting me."
Rhys claimed awards for best comedy actor for Widow's Bay and for best actor in a limited series for the Netflix psychological thriller The Beast in Me.
In other awards, Widow's Bay star Stephen Root upset favourite Harrison Ford of Shrinking for best supporting actor in a comedy.
Allison Janney won best supporting actress in a drama over Katherine LaNasa from The Pitt, who won last year, and three of her castmates.
Janney joined Smart as an eight-time Emmy winner.
The Late Show with Stephen Colbert, which was cancelled by CBS and aired its final episode this year, won best variety series.
It's one of six Emmys the show has won this year after the show was cancelled for what the network said was economic reasons while many believe it was his criticism of the Trump administration.
Best drama actress went to Rhea Seehorn, who plays a misanthropic woman at war with an unfailingly kind alien hive mind on the new Apple TV series Pluribus.
It was her first Emmy win. Seehorn addressed her fellow nominees, with a quote from the feminist activist Gloria Steinem, who died this month aged 92.
"We are linked, not ranked. I feel that way about all you women," Seehorn said.
The academy honoured Michael J Fox during the ceremony for his advocacy for Parkinson's disease research and treatment.
Fox said support from Hollywood had allowed him to keep acting after his own diagnosis with Parkinson's.
"It's because you stood up for me," he told the crowd.
Mariska Hargitay, star of Law & Order: Special Victims Unit, hosted the ceremony on Monday.
"It's a lot of pressure, but it is so reassuring to see so many familiar faces out there, and I'm not just talking about how many of you I've arrested on SVU," Hargitay told the crowd.
Australia's Sarah Snook was nominated for thriller All Her Fault but lost to Hollywood veteran Sally Field.
Field, 79, became the oldest woman to win best actress in a limited or anthology series or TV movie for Remarkably Bright Creatures.
The Emmys offered a rare night of celebration as Hollywood grapples with production cutbacks, anxiety over artificial intelligence and the proposed Paramount Skydance purchase of HBO owner Warner Bros. Discovery, a deal that has divided the industry and faces legal challenges.
Winners largely avoided potentially divisive topics in their acceptance speeches and stuck to thanking their families and co-stars.
