Mr Zuckerberg called for students to "not only create new jobs, but create a new sense of purpose".
Political experts think he may be positioning himself to run for office.
During his remarks on Thursday, Mr Zuckerberg told graduates that "we live in an unstable time".
"There's pressure to turn inwards," he said about those that feel left behind by increased globalisation.
Zuckerberg, seated beside actor James Earl Jones, received an honorary Doctor of Laws degree
"This is the struggle of our time. The forces of freedom, openness and global community against the forces of authoritarianism, isolationism and nationalism."
With his wife, Priscilla, in the audience, he pointed to the dormitory where he launched Facebook, and remarked that meeting her there was the best thing to happen to him at the university.
Before giving remarks, he received an honorary Doctor of Laws degree during Harvard's 366th graduation ceremony.
On Wednesday, he did a Facebook Live broadcast from his old dorm room.
"This is literally where I sat," he says, pointing to a small wooden desk and chair inside Kirkland House, which is due to be renovated over the summer.
"I had my little laptop here. And this is where I programmed Facebook," he tells the camera.
During his commencement address, Mr Zuckerberg told students: "There is something wrong with our system when I can leave here and make billions of dollars in ten years when millions of students can't afford to pay off their loans, let alone start a business.
"When you don't have the freedom to take your idea and turn it into a historic enterprise we all lose," he continued.
He told stories of meeting "children in juvenile detention and opioid addicts, who told me their lives could have turned out differently if they just had something to do".
The 33-year-old appeared to get choked up at one point during a story about an high school student who feared he would not be able to enrol in university because he was an undocumented immigrant.
More than 1.9 billion people log onto Facebook every day.
Since it's launch in 2004, Facebook has inspired many other social media competitors, including Twitter, Snapchat, and Instagram.
In 2007 another Harvard drop-out returned for an honorary degree.
Bill Gates addressed students shortly after stepping down from the world's largest software company, Microsoft, to launch to focus on his charity.
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