Pence urged the graduates to "hold onto your calling" and quoted Jeremiah 29:11 from the Bible.
"Never let it go," Pence added, discussing his own path through politics that saw him rise from a congressman to Indiana governor and eventually the vice presidency. "Persistence, men and women. Hold onto your dreams."
Roughly 4,500 students attended the event at Grove City, a Christian liberal arts college located about 50 miles north of Pittsburgh.
Pence is also expected to deliver remarks for Armed Forces Day Celebration at Wright-Patterson Air Force Base near Dayton, Ohio, in addition to the commencement speech at the University of Notre Dame.
Student activists at Notre Dame are planning to walk out of Pence's speech Sunday, where he will receive an honorary degree.
"During his time as governor of the state of Indiana and now as Vice-President, Pence has targeted the civil rights protections of members of LGBT community, rejected the Syrian refugee resettlement program, supported an unconstitutional ban of religious minorities, and fought against sanctuary cities," student activist coalition We StaND For said in a statement. "All of these policies have marginalized our vulnerable sisters and brothers for their religion, skin color, or sexual orientation."