Smart played Deborah Vance, a septuagenarian comedian fighting to stay relevant, on Hacks. The show aired its final season on HBO Max this year.
"What a ride this has been!" Smart said on stage after thanking the show's creators.
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.
Supporting comedy actress went to Kate O'Flynn, who plays a quirky mayoral assistant on the Apple TV horror comedy Widow's Bay.
The Emmy ceremony got underway on Sunday night (10am AEST Monday) in Los Angeles.
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.
Mariska Hargitay 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.
Other presenters will include Jon Hamm, Sally Field, Amy Poehler and Zendaya.
"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.
Hargitay said she worked with writers from Stephen Colbert's former late-night show to craft Emmys material.
"To spend time in a room full of brilliant comedy writers and be in this just joy and celebration, it's very different from what I do," Hargitay said ahead of the ceremony.
Nicole Kidman is another Australian nominated - for executive producer in the Apple TV comedy series Margo's Got Money Troubles.
The Emmys offer 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.
HBO Max's The Pitt, set in a Pittsburgh trauma centre, is favoured to win best drama - the night's top award - for a second straight year.
Competitors include newcomer Pluribus, an Apple TV show about a woman at war with an alien hive mind.
Australia's Shabana Azeez, who stars as medical student Victoria Javadi in The Pitt, walked the blue carpet on Sunday in a golden sheath dress.
Her Pitt co-star star Noah Wyle is a leading contender for a second straight best actor Emmy.
The night could also bring the first Emmy - and first major competitive Hollywood award of any kind - to 84-year-old Harrison Ford, who is among the favourites for best supporting actor in a comedy for playing a therapist coping with Parkinson's disease on Shrinking.
