Johnnetta Betsch was born in Jacksonville, Florida, on October 19, 1936. She enrolled in Fisk University at the age of 15, and after the completing the first year, transferred to Oberlin College in Ohio, where she completed a Bachelor of Arts degree in sociology in 1957. Dr. Cole attended graduate school at Northwestern University, earning her Master of Arts and Doctor of Philosophy degrees in Anthropology. Dr. Cole served as a professor at Washington State University from 1962 to 1970, where she co-founded one of the US's first black studies programs. In 1970, she began working in the Department of Anthropology at the University of Massachusetts Amherst, where she served until 1982. She then moved to Hunter College and became director of the Latin American and Caribbean Studies program. In 1987, Dr. Cole was selected as the first black female president of Spelman College where she served until 1997. From 1998 to 2001 Cole was a professor of Anthropology, Women's Studies, and African American Studies at Emory University in Atlanta. After teaching at Emory University, she was recruited as president of Bennett College for Women, also a historically black college for women.

She was Director of the National Museum of African Art, part of the Smithsonian Institution in Washington, DC, from 2009 until 2017. Dr. Cole is the recipient of more than 50 honorary degrees and numerous accolades and has served on many boards. During her Spelman presidency, she was the first woman elected to serve on the board of Coca-Cola Enterprises.

Dr. Cole is also an author of numerous books.