The philanthropist encouraged the girls to be "open to hear the truths of others."
The OWN Network CEO was the commencement speaker for the all-women college in the northern Georgia.
"My daughter-girl has had the great privilege of growing and blossoming here at Agnes Scott," she said about Sithoko, who came from her South African school.
"And I want you to know at my school, the Oprah Winfrey Leadership Academy for Girls, every year we're graduating another class of girls. I now have another 179 girls in college... I have five different graduations next week, in four different states. So, Agnes Scott, you got me fresh."
Per usual, Winfrey blessed the crowd with wise words of encouragement but was hilarious at the same time.
"I've made a living, I've made a life, I've made a fortune, really. It's fantastic," she said to the laughing crowd. "The biggest reward is not financial benefits, although it's really good. You can get a lot of great shoes... But living a life of substance... substance through your service —your offering of your whole self."
She also pulled from her journalism background to encourage the girls to be authentic, but open to understanding other's perspectives.
"I want you to work in your own way to change the world in respectful conversations with others, at a rate and a rhythm that's in tune with the source from which you have come. Your truth."
Adding, "And I want you to enter every situation aware of its context. Open to hear the truths of others. And most important, open to letting the process of changing the world, change you."