Accounts posting the footage said the students at the prestigious university were protesting the usually apolitical star's stance over Israel, which has drawn controversy. Students could be seen carrying a Palestinian flag.
It is the latest unrest over the war to rock US campuses, which have become a political flashpoint after weeks of protests that have seen thousands arrested.
A live feed from Duke of the graduation ceremony did not show the walkouts, but boos were audible, forcing university president Vincent Price to briefly halt his introduction of Seinfeld as the comedian stood next to him.
Seinfeld accepted the honorary degree to cheers, and delivered the school's commencement address without further interruption.
The 70-year-old did not allude to the war, and touched on being Jewish only briefly, in a riff about privilege.
"I grew up a Jewish boy from New York. That is a privilege if you want to be a comedian," he said.
Duke had earlier said that degrees would be awarded to some 6,900 students during the ceremony, though it was not clear how many attended in person.
For decades, Seinfeld has been a resolutely apolitical comedian, best-known for making one of the most beloved sitcoms of all time -- a show, bearing his name, that was famously "about nothing."
But he has been unusually outspoken over his support for Israel since the fighting in Gaza began, drawing controversy.
He traveled to Tel Aviv in December to meet with the families of hostages taken by Hamas militants in their October 7 attack on Israel. When asked by GQ magazine about his motivation for the trip, he replied: "Well, I'm Jewish."
He and his wife Jessica have also been active on social media against anti-Semitism in the United States.
Police have arrested more than 2,000 people nationwide in the recent weeks of campus unrest. The demonstrations have also spread overseas, including to France and Canada.
Students have been protesting Israel's war against the Palestinian militant group Hamas in Gaza, and demanding that their schools divest financially from US weapons manufacturers and Israeli entities.
Campus authorities have sought to support the right to protest while acting against complaints of anti-Semitism and hate speech at the demonstrations.
In at least one incident, counter-protesters physically attacked demonstrators at the University of California, Los Angeles. Jessica Seinfeld announced recently on Instagram that she had donated money to fund counter-protests at UCLA.
The Duke walkout came a day after dozens of students at Virginia Commonwealth University also walked out of their graduation ceremony as state governor Glenn Youngkin delivered the commencement address.
Reports suggested they were demonstrating support for Palestinians and protesting other policies by the governor on education and racial equality.
