Modern Family, ABC's show about the chaotic lives of three related couples and their children, won best comedy series for a third year and supporting actor Emmys for Eric Stonestreet and Julie Bowen, as well as a directing award.
"I am praying that everyone doesn't get sick of us," joked executive producer Steve Levitan.
Backstage, Stonestreet joked, "We know that eventually it will not be this way and you will hate us all."
Homeland, a post 9/11 psychological thriller about a returning Iraq war hero turned by al-Qaeda, won best drama after one season on cable channel Showtime. It also took home trophies for best writing and best acting for its two leads, Claire Danes and Damian Lewis, for a total of six including technical awards.
Homeland, said to be one of President Barack Obama's favourite TV programmes, brought to an end the reign of AMC's stylish 1960s advertising show Mad Men, which left Sunday's Emmy ceremony empty-handed.
It was the biggest shutout in Emmy history for Mad Men, which had gone into Sunday's awards as joint top nominee with 17 nominations.
Homeland also beat popular Downton Abbey, about aristocrats and their servants in an English country house, and HBO's medieval fantasy series Game of Thrones, in what was the first year that all the nominated best drama series came from cable television.
Age of anxiety
Danes, who plays a bipolar CIA operative in a cat-and-mouse game with Lewis's sleeper agent, said she believed Homeland had succeeded with viewers and critics because it was neither preachy nor overtly political.
"We are a little startled. I don't think anyone was expecting to be recognised this way starting off," Danes told reporters backstage.
"[The show] doesn't take a very biased position [but] it does speak to our feelings of anxiety and unrest right now, in the sense that we're in a new era where the enemy is not so clear."
Danes said it was "way cool" that Obama is a fan. "I think it speaks to the relevancy of the show, and it's hugely validating," she added.
Homeland returns for a second season on September 30, with an opening episode set against the fictional bombing by Israel of Iranian nuclear facilities and the global tensions that ensue.
American politics did figure strongly in other Emmy races. Game Change, the HBO story of Sarah Palin's entry into the 2008 US vice presidential race, was also a big winner, taking the Emmy for best miniseries, writing, directing and acting for star Julianne Moore.
"Wow, I feel so validated because Sarah Palin gave me a big thumbs down!" Moore said while accepting her first Emmy.
Backstage Moore thanked actress and Palin impersonator Tina Fey, and journalist Katie Couric for what she called their "incredible influence" on the 2008 elections. Couric interviewed Palin in 2008 in what became a cultural and political landmark after the encounter was spoofed by Fey on Saturday Night Live.
In what was seen as a tight race for lead comedy actress, Julia Louis-Dreyfus beat Girls star Lena Dunham, Amy Poehler, New Girl Zooey Deschanel and Tina Fey with her turn as a frustrated US vice president in the wickedly satirical HBO political show Veep.
"It's a bit mystifying to me because people say this show is a comedy, but I don't see anything funny about me being vice president of the United States," the former Seinfeld star quipped.
With the presidential elections less than two months away, Emmy show host Jimmy Kimmel got the festivities off to a biting and topical start in an opening monologue.
Kimmel joked that US television was "the only American product the Chinese haven't figured out how to make".
As for the sprawling grandeur of Downton Abbey, Kimmel quipped, "It really gives you a sense of what it must have been like to grow up in [US Republican presidential candidate] Mitt Romney's house."
Two and A Half Men's Jon Cryer was the surprise winner in the comedy actor category, beating fellow CBS nominee and double Emmy winner Jim Parsons of geeky show The Big Bang Theory.
Stand-up comedian Louis CK went home with his first two Emmys – one for writing for his FX show Louie, in which he also stars as a divorced dad, and another for directing his own TV stand-up special.
Oscar-winning actor Kevin Costner won an Emmy in his first role for television. Costner starred in the popular History channel miniseries Hatfields & McCoys, about a legendary feud between two 19th century families, while Tom Berenger took a supporting actor Emmy for his role in the show.
"I'm a writer-orientated actor and when I find the writing, I don't care what medium it sits," Costner told reporters on Sunday of his move to television.
The Amazing Race won for the best reality series Emmy for the ninth time, while Tom Bergeron won best reality host for Dancing with the Stars.
Here are the key winners at the Primetime Emmy Awards:
Here is a list of winners in the main categories at the 64th Annual Primetime Emmys, US television's annual awards show held Sunday in Los Angeles. Best drama: Homeland
Best comedy: Modern Family
Best miniseries or movie: Game Change
Best drama actress: Claire Danes, Homeland
Best drama actor Damian Lewis, Homeland
Best drama supporting actress: Maggie Smith, Downton Abbey
Best supporting actor: Aaron Paul, Breaking Bad
Best drama director:Tim Van Patten, Boardwalk Empire
Best drama writer: Alex Gansa, Howard Gordon, Gideon Raff, Homeland
Best comedy actress: Julia Louis-Dreyfus, Veep
Best comedy actor: Jon Cryer, Two And A Half Men
Best comedy supporting actress: Julie Bowen, Modern Family
Best comedy suporting actor: Eric Stonestreet, Modern Family
Best comedy director: Steven Levitan, Modern Family
Best comedy series writer: Louis CK
Best miniseries or movie actress: Julianne Moore, Game Change
Best miniseries or movie actor: Kevin Costner, Hatfields & McCoys
Best miniseries or movie supporting actress: Jessica Lange, American Horror Story
Best miniseries or movie supporting actor Tom Berenger, Hatfields & McCoys
Best miniseries or movie director: Jay Roach, Game Change
Best miniseries or movie writer: Danny Strong, Game Change
Best variety series: The Daily Show With Jon Stewart – Reuters, Sapa