After walking away empty-handed from last year's Emmys and January's Golden Globes, many suspected Mendelsohn would be bested once again by one of two "Game of Thrones" nominees - Peter Dinklage or Kit Harington.
But Mendelsohn's chilling portrayal of an outcast family member in the Netflix series "Bloodline" has been recognised at the ceremony in Los Angeles, which he did not attend.
"Game of Thrones" did end up winning the Best Drama Emmy for the second year in a row, while "The People vs. OJ Simpson" took out nine awards, including Best Limited Series.
Tatiana Maslany won Best Actress in a Drama for "Orphan Black", while Rami Malek took out Best Actor for "Mr. Robot".
'Veep' wins best comedy
Jeffrey Tambor won best actor in a comedy for "Transparent", where he thanked Jill Soloway who won best comedy director.
"You changed my life, you changed my career and you changed everything," he said.
As the reigning champ in the category, Tambor was the frontrunner from the start of Emmy season. He's received a tidal wave of kudos for his portrayal of the transgender Maura Pfefferman.
He ended his speech by asking creatives to give "transgender talent a chance."
"Give them auditions," he said. "Give them their story. Do that.
"I would not be unhappy if I were the last cisgender male to play a female transgender on television, we have work to do."
Meanwhile, actor Aziz Ansari broke into the Emmy race in a big way, winning best writing for his autobiographical Netflix comedy "Master of None".
But the gong for Best Comedy Series went to "Veep", starring Julia Louis-Dreyfus. Earlier, she had won her fifth lead actress in a comedy Emmy, which she dedicated to her late father, William Louis-Dreyfus.
"I'm so glad he liked "Veep," because his opinion was the one that really mattered," she said during an emotional acceptance speech.
Former GOP presidential candidate Jeb Bush even made a surprise appearance during host Jimmy Kimmel's opening sketch.
Bush was the limo driver for Julia Louis-Dreyfus' character in "Veep".
"Are you nominated?" Bush asks Kimmel. "Wow, what's that like?"
"If you have a positive campaign, the voters will ultimately make the right choice," he joked.
