He started his career by heading his father's bank, the Bank of North Carolina, merged it with NCNB in 1982, and eventually with Bank of America. From 1982 to 1986 he served as chair of North Carolina's Board of Education. He then served as President of his alma mater, the University of North Carolina, from 1986 to 1997.
He served as President of Harvard University's Board of Overseers from 2003 to 2004. The Spangler Center at Harvard Business School is named for him. Through his C.D. Spangler Foundation, he has donated to the University of North Carolina, Harvard University, and to Charlotte's Teach for America. As a hobby, he likes to fix old clocks.