Smart became the first performer to claim the trophy for best comedy actress for every season of a show's run, winning a total of eight Emmys in her career. Hacks aired its final season on HBO Max this year.
The audience rose for a standing ovation as Smart, 75, made her way to the stage for her fifth victory as legendary Las Vegas comedian Deborah Vance. Smart immediately turned the moment into material.
"Just the men stay standing. The girls get to sit down," she joked.
"What a ride this has been!" Smart said.
Wyle said it felt "overwhelming" to land his second straight Emmy for playing Dr Robby Robinavitch on The Pitt, a medical drama set in a Pittsburgh trauma centre. The show is seen as the frontrunner for the night's top award of best drama.
Describing himself as a "Hollywood kid," Wyle told the audience, "this is the only club I've ever wanted to join. Thank you for accepting me".
Allison Janney tied the record for most Emmys won by a performer for her portrayal of US President Grace Penn in The Diplomat.
The 66-year-old took home her eighth award at the annual event, scooping the Outstanding Supporting Actress in a Drama Series prize and matching the record previously set by Julia Louis Dreyfus and Cloris Leachman and equalling the record set earlier in the evening by Smart.
"This is not what I planned for this category at all," a visibly stunned Janney said.
"I am so grateful and so lucky. And I thank you very much from the bottom of my heart."
In other awards, Widow's Bay star Stephen Root upset favourite Harrison Ford of Shrinking for best supporting actor in a comedy.
Best drama actress went to Rhea Seehorn, who plays a misanthropic woman at war with an alien hive mind on the new Apple TV series Pluribus.
It was her first Emmy win. Seehorn addressed her fellow nominees, including The Diplomat star Keri Russell and Zendaya of Euphoria, 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 Emmy ceremony got underway on Sunday night (10am AEST Monday) in Los Angeles.
Mariska Hargitay, star of NBC's drama Law & Order: Special Victims Unit, opened the NBC telecast with a musical tribute to television viewing, I Love TV Screens, sung to the tune of I Love Rock 'n' Roll.
"NBC is celebrating its 100th year, and I have been on Law & Order: SVU for all of them," said Hargitay, a three-time Emmy winner who has starred in the show for 27 seasons.
Supporting comedy actress went to Kate O'Flynn, who plays a quirky mayoral assistant on the Apple TV horror comedy Widow's Bay.
Australia's Sarah Snook is nominated twice - for outstanding lead actress and producer - in the limited series All Her Fault.
Snook is no stranger to the winners' podium after taking home an Emmy in 2024 for her role as Shiv Roy in the series Succession.
Matthew Rhys made history becoming the first person to win two lead acting Emmy Awards at one ceremony.
The 51-year-old star's evening began with a surprise win in the Outstanding Lead Actor in a Limited or Anthology Series or Movie category for his role in The Beast in Me.
He then took the Outstanding Lead Actor in a Comedy Series prize for Widows Bay, and after previously securing the Drama Actor prize in 2018 for the Emmys, he is now the first male performer to have won in all three lead categories.
with AP and Bang
