Her work has primarily involved the stories of Black women and communities in the Appalachian and rural Southern canon.

Wilkinson wrote that she "lived an enchanted childhood" and that her grandparents "gave me the freedom to explore the countryside and to write, to dream, to discover.

In 2003, she earned her Master of Fine Arts degree for Creative Writing from Spalding University in Louisville, Kentucky.

During this time, Wilkinson joined other Kentuckian African American writers (including Kelly Norman Ellis,[7] Ricardo Nazario y Colon,[8] Mitchell L. H. Douglas,[9] and Daundra Scisney-Givens)[10] at the Martin Luther King Jr.

As of 2020, Wilkinson is an associate professor at the University of Kentucky in the Department of English, the Program in African American and Africana Studies.

Her short fiction piece "Holler", published in Slice Literary Magazine (Spring/Summer 2010), was nominated for the 2010 Pushcart Prize.

Crystal Wilkinson has also gained recognition from the United States Artists in being awarded a position as a 2020 USA Fellow.