Benioff was raised in a Jewish family in the San Francisco metropolitan area. He graduated from Burlingame High School in 1982. Benioff received a Bachelor of Science in Business Administration from the University of Southern California in 1986, where he was a member of the Tau Kappa Epsilon fraternity.

Benioff is a noted philanthropist. In 2000, he established the “1-1-1 model,” whereby the company contributes one percent of product, one percent of equity, and one percent of employee hours back to the communities it serves globally. As of March 2016, Salesforce.org has delivered more than $115 million in grants, 1.3 million employee volunteer hours and is used by 28,000 nonprofit organisations with Salesforce Technology. More than 700 companies have adopted the 1-1-1 model through the Pledge 1% movement. Benioff and his wife, Lynne, have focused their personal philanthropy on improving public education and advancing children’s health care through UCSF Benioff Children's Hospital, at the University of California, San Francisco.

Benioff created the 1-1-1 model of integrated corporate philanthropy, by which companies contribute 1 percent of equity, 1 percent of employee hours and 1 percent of product back to the communities it serves. Parts of this 1-1-1 model have been adopted by more than 700 companies, including Google. In 2005, the members of the World Economic Forum named him as one of its Young Global Leaders. In 2007, the Committee Encouraging Corporate Philanthropy presented Benioff with the Excellence in Corporate Philanthropy Award and in 2008 invited him to become a Director of the board.

In June 2010, Marc Benioff and his wife Lynne announced a $100-million gift to UCSF Children's Hospital with the goal of not only seeing the new hospital built but significantly advancing children's Health care worldwide. The Benioffs have been recognized as top Philanthropists by Forbes' America's 50 Top Giver list in 2015 and the Chronicle of Philanthropy's Philanthropy 50 list in 2010, 2014 and 2015.

In 2014, Marc and Lynne Benioff donated another $100 million to UCSF and Oakland Children's Hospital (both now called Benioff Children's Hospitals). Marc and Lynne Benioff have also donated to The Ocean Cleanup, a non-profit organization developing technologies to rid the world's oceans of plastic.

In April 2015, Benioff announced that he would be reviewing all salaries at Salesforce to ensure men and women were being paid equally for comparable work. On the heels of the salary assessment, Benioff joined President Barack Obama in January 2016 as he celebrated the anniversary of the Lily Ledbetter Fair Pay Act and renewed his call on Congress to pass the Paycheck Fairness Act.

Benioff supported Hillary Clinton for President of the United States in the 2016 presidential election.

On March 17, 2017, Benioff was included in a Business leaders' symposium organized by the Trump Administration during German Chancellor Angela Merkel's visit to the White House.

In March 2018, Benioff announced that he would be donating 1 million USD to March for Our Lives. In the announcement, Benioff wrote, "Motivated to join the many who are passionate about the safety of all kids and I’ll give $1 million to March For Our Lives. Together all of us can make children’s health and safety our number one priority. Join us and March on March 24th."

Benioff has said that businesses are the greatest platforms for change in the world. He follows the World Economic Forum founder Klaus Schwab’s multistakeholder approach to leadership, which says that Leaders should serve not only their shareholders but all stakeholders, including customers, employees, partners, communities and the environment, to make the world a better place.