During her 25-minute speech beneath overcast skies, the talk show host told the 4,400 graduates and their guests that "one of the best ways to enhance your own life is to enhance somebody else's" and to "stand proudly in your own shoes while you help others stand in theirs."
"How can I help somebody else move to higher ground? That is success. That's it. That's why we're all alive," she said.
She also emphasized the need to make wise choices daily, saying, "Each of us has to stand in our own shoes. Will you stand in them in humility and compassion and courage? Every day will give you a chance to make that choice."
Duke President Richard H. Brodhead presented Winfrey with an honorary doctor of humane letters degree.
She also had a personal connection with the 2009 class at the Durham, N.C., school. Her godson, William Bumpus, son of her well-known friend, Gayle King, was among the graduates.
"Will never wants people to know he knows me," Winfrey joked. "I'm like his crazy aunt that they let out at commencements."
Preceding Winfrey was student speaker Robert Paul Jones, a 2002 graduate who returned to Duke to receive his medical degree. He teased her about her celebrity, and pretended to be interrupted by a cell phone call as he began his remarks.
"Ms. Winfrey, apparently your limousine is double-parked in front of the chapel," Jones joked. "Duke Parking wanted me to let you know they won't release your honorary degree until you pay your parking fine."