Ellen previously described herself as a vegan and "big animal lover". De Rossi, too, is a vegan. Ellen co-ordinated a vegan outreach website titled 'Going Vegan with Ellen'. She intended to open a vegan tapas bar, Bokado, in Los Angeles, but plans fell through.

The site for The Ellen DeGeneres Show contains a section called "Going Vegan With Ellen", in which she promotes "Meatless Mondays" and features vegan recipes. She has several times invited Humane Society of the United States CEO Wayne Pacelle to speak on her show about the organization's efforts in animal protection legislation. In 2009, PETA named her their "Woman of the Year." In April 2013, she donated $25,000 to stop Ag-Gag anti-whistleblower legislation in Tennessee, which would prohibit undercover investigators from recording footage of animal abuse on farms.

DeGeneres served as campaign ambassador to Farm Sanctuary's Adopt-A-Turkey Project in 2010, asking people to start "a new tradition by adopting a turkey instead of eating one" at Thanksgiving.

In November 2011, Secretary of State Hillary Clinton named her a special envoy for Global AIDS Awareness.[86] On December 3, 2011, DeGeneres opened the show at the David Lynch Foundation's 3rd annual "Change Begins Within" gala at the Los Angeles County Museum of Art to raise funds to bring Transcendental Meditation to at-risk populations suffering from epidemic levels of chronic stress and stress-related disorders. She says: "TM is the only time I have that stillness… it gives me this peaceful feeling, and I love it so much. I can’t say enough good things about it. All the benefits that you can achieve from sitting still and going within—it really is a beautiful experience. David Lynch is such a wonderful man to start this foundation to help people."

In November 2017, it was announced that President Donald Trump would begin allowing the importation of elephant trophies from Africa. DeGeneres, an animal activist, created a hashtag campaign in partnership with her brand, ED Ellen DeGeneres, to donate to the David Sheldrick Wildlife Trust. DeGeneres also created a t-shirt with her brand whose proceeds also go to the organization.

In January 2018, for Ellen's 60th birthday, Ellen's wife, Portia de Rossi, gifted Ellen a permanent gorilla home in Rwanda built in her namesake for the Digit Fund. This gift was part of a new arm of the Digit Fund now called the "Ellen DeGeneres Wildlife Fund.