As expected, Leto won for his acclaimed performance as a transsexual in the Texas AIDS drama "Dallas Buyers Club." He dedicated his award to his mother, his date on the night.
"Thank you for teaching me to dream," said Leto.
Sunday's Oscars hung on a nail-biter of a finish, with the best picture race believed to be between the historical drama "12 Years a Slave," the 3-D space spectacle "Gravity" and the con-artist comedy "American Hustle." DeGeneres alluded to the options in her opening monologue.
"Possibility number one: '12 Years a Slave' wins best picture," she said. "Possibility number two: You're all racists."
Her opening went over well in Los Angeles' Dolby Theatre, which had far more mixed reactions to last year's host, Seth MacFarlane. She chided Leto ("Boy, is he pretty") and mocked Jennifer Lawrence for falling on her way onto the red carpet, just as she did when she accepted the Oscar last year for "Silver Linings Playbook."
Just as Lawrence hit the carpet and waved to fans, she collapsed in a heap of her red dress, laughing at herself.
"If you win tonight, I think we should bring you the Oscar," said DeGeneres to Lawrence, nominated for her performance in "American Hustle."
Though the Oscar ceremony is usually a glitzy bubble separate from real-world happenings, international events were quickly alluded to. In his acceptance speech, Leto addressed people in Ukraine and Venezuela.
"We are here and as you struggle to make your dreams happen, to live the impossible, we're thinking of you," said Leto.
Russian state-owned broadcaster Channel One Russia said it would not broadcast the Oscars live because of the necessity for news coverage of Russia's invasion of Ukraine's Crimea peninsula. It will instead transmit the Oscars early Tuesday morning, local time.
Venezuelan protesters, via social media, urged Oscar winners to bring attention to their plight. Anti-government protests have roiled the country in recent weeks.
DeGeneres gently mocked Hollywood's insularity, referring to the headlines that have swamped the Los Angeles area lately with a slightly less serious news event.
"It has been raining," said DeGeneres. "We're fine. Thank you for your prayers."
After a blustery few days of torrential downpours, Hollywood was ready for smooth sailing - in DeGeneres' less controversial hosting and a crop of seemingly sure-fire winners - at Sunday's show.
Best-actor nominee Matthew McConaughey was greeted by fans in bleachers along the red carpet humming and patting their chests as he does in "The Wolf of Wall Street." Lupita Nyong'o, the "12 Years a Slave" nominated star and new red carpet favorite, wore a flowing ice blue Prada gown that she said reminded her of her Kenyan home.
The Oscars promise a music-filled ceremony, including the best-song favorite "Let it Go," sung by Broadway's Idina Menzel in Disney's "Frozen": "If I wasn't nervous, something would be a little off," said Menzel on the red carpet.
The well-established favorites include McConaughey, Cate Blanchett and Nyong'o. Each comes into Oscar Sunday having won a parade of awards over the last few months, including honors at Saturday's Spirit Awards.
"Gravity" is expected to lead the ceremony in total awards, cleaning up in technical categories like visual effects and cinematography. Mexican filmmaker Alfonso Cuaron is considered a lock for best director for seamlessly marshalling new digital technology to render the lost-in-space drama. He would be the first Latino filmmaker to win the category.
While the global hit easily topped the other eight best-picture nominees at the box office, the lower budget, less widely seen "12 Years a Slave" is believed to have a narrow edge for the academy's top honor.
Though voters last year chose entertainment over history lesson (Ben Affleck's "Argo" over Steven Spielberg's "Lincoln"), many see Steve McQueen's brutal adaptation of Solomon Northup's memoir as a landmark film difficult to watch but impossible to overlook.
ABC, which is telecasting the ceremony, hopes the drama of the best-picture race will be enough to entice viewers. The show last year drew an audience of 40.3 million, up from 39.3 million the year before when the silent-film ode "The Artist" won best picture.