The star, who is of Egyptian heritage, won the prize for his role in the USA Network drama Mr Robot.
He said he hoped his win would open the door for more ethnic minority actors.
"For me to stand here as not the typical leading man and to have come home with this speaks a lot about where we’re headed," he said.
"I think we can keep going a lot further in that direction, not just in entertainment, but socially and politically, and strive to be as progressive as possible."
Malek held off competition from actors including bookmakers’ favourite Kevin Spacey, who was nominated for House of Cards, The Americans’ Matthew Rhys and Better Call Saul star Bob Odenkirk.
The last non-white winner to win the trophy was Andre Braugher for Homicide: Life on the Street in 1998.
Since then, the winners have included James Gandolfini for The Sopranos, Damian Lewis for Homeland, The Shield’s Michael Chiklis, Jeff Daniels for The Newsroom and Breaking Bad’s Bryan Cranston.
In his acceptance speech, Malek said: "I’m honoured to stand here and represent my family and every single person who’s helped me get this far."
Referring to his surprise win, he joked to the audience: "Please tell me you’re seeing this too."
Malek was born in Los Angeles in 1981 to Egyptian parents. He went to Notre Dame High School in Sherman Oaks, California - graduating in 1999 along with fellow actor Rachel Bilson.
In 2004, Malek got his first major TV role in Gilmore Girls and went on to appear in 24, The Pacific, Over There and The War at Home.
His film roles to date include Larry Crowne, Twilight: Breaking Dawn - Part 2, a recurring role in the Night At The Museum series.
Malek began starring in Mr Robot in 2015, a role that has also netted him a Critics’ Choice Award.
Malek was one of several ethnic minority actors to triumph at Sunday’s ceremony.
Courtney B Vance and Sterling K Brown, who both appeared in The People vs OJ Simpson, won the best leading actor and supporting actor in a limited series categories respectively.
And Regina King was named outstanding supporting actress in a limited series or movie for her role in American Crime.
Meanwhile, Alan Yang and Aziz Ansari called for better Asian representation on screen after winning the Emmy for outstanding writing for a comedy series for Netflix series Master of None.
Host Jimmy Kimmel made several references to diversity during the ceremony in light of the "Oscars So White" controversy earlier this year.
"Here in Hollywood the only thing we value more than diversity is congratulating ourselves on how much we value diversity," he said in his opening monologue.
"The Emmys are so diverse this year the Oscars are now telling people we’re one of their closest friends."
He joked that the ceremony was almost too diverse - with other notable winners including Susanne Bier, who was the only woman nominated in her category of best limited series director.
Kate McKinnon, Saturday Night Live’s first openly lesbian cast member, also won her category of outstanding supporting actress in a comedy series.
- Rami Malek said the US can become ’more progressive’ in entertainment, society and politics