Buckhanon was born in Kankakee, Illinois. Her mother Juwana was 15 and her father Kerry Buckhanon 16; she lived with both sets of grandparents as an infant. Her parents wed in 1980. After beginning with menial jobs, both worked up to professional positions, her mother in food services management and her father in social work.

Buckhanon attended St. Theresa's Catholic School where she took advanced placement classes. At ten, with her parents unable to afford continued private education, she began attending public schools in Kankakee School District 111 (New York Daily News, January 14, 2005). Kalisha was a stand-out student in the district, winning scholarships and awards. She excelled in academics and the arts, studying piano throughout high school and taking classes in drama and dance. She entered the Illinois Young Authors Commission Annual Competition each year she was eligible, until she won at the age of 12 for her short farce "The Battle for the Blue Room." She was also recognized by the NAACP for her play entitled Almost Dawn, which won a 2nd-place NAACP ACT-SO Award when Kalisha was 15. When she was 16, she appeared on the nationally syndicated Jane Whitney Show in New York City. The local NAACP, frustrated with the lack of diversity of the school district's mostly white faculty in a majority Black town, had begun a movement to segregate the schools in protest of local hiring practices. Instead of joining the boycott against the local public schools, Buckhanon continued to attend school and wrote to the local newspaper in support of a solution which would not require school segregation...which she believed would be a step backwards. The letter caught the attention of New York City talk show producer who had been following the controversy. Kalisha defended her ideas against guest panelists, including former Ku Klux Klan Grand Wizard David Duke, on the October 1993 broadcast (Kankakee Sunday Journal, November 23, 2003).

Buckhanon won academic scholarships from the Daughters of the American Revolution, SCORE, NAACP, Zonta, the Elks and many other entities for her outstanding high school performance. She turned down admission offers to Columbia, Yale and Northwestern Universities to stay close to home and attend the intellectually rigorous University of Chicago, where she thrived despite working at times up to three jobs. She served as a teaching assistant in local elementary schools and taught reading and writing in several community organizations, including Southwest Women Working Together's Shelter for Battered Women and Children. She earned a Mellon Minority Undergraduate Fellowship in 1997 and began to study Black women's literature, culture and film. She worked with such professors as Jacqueline Stewart (PhD University of Chicago), Kenneth Warren (PhD Harvard) and Deborah Nelson (PhD Yale) on several projects related to the exploration of identity, race and gender in cultural productions (Urbanreviews.com, Inside Out With Kalisha Buckhanon). She helped resurrect the University's defunct Black Light newsletter, a publication of the Organization of Black Students. She also served on event committees which helped to bring such Black writers as John Edgar Wideman, Gwendolyn Brooks, Derek Walcott, Nikki Giovanni, Sonia Sanchez and Angela Davis to Campus. She graduated magna cum laude from the University of Chicago in 1999, having been elected into Phi Beta Kappa and becoming a Student Marshal, a designation reserved for the top 2% of any graduating class.

Despite numerous graduate opportunities, Buckhanon chose to pursue her creative writing more seriously. She worked as a waitress, coffee shop server, medical secretary and PR intern in Chicago while she wrote her first novel, The Junction (London Observer, June 12, 2005, p. 6). She obtained her first official journalism credit when she profiled tap dancer Bril Barrett and his company MADD Rhythms for RollingOut Urbanstyle Weekly. Eventually, she found work as a Communications Specialist for the National Black MBA Association; she honed her skills in PR, speech writing, media relations and worked on events featuring such luminaries as the Reverend Jesse Jackson, Maya Angelou and former NBMBAA CEO Antoinette Malveaux. She also served as a contributing writer (2000—2002)and assistant editor of Black MBA Magazine (2002—2003).She secured a top literary agent for The Junction, but the agent was unable to sell the historical novel about three generations of Black women living in a place similar to Kankakee (Black Issues Book Review, March-April 2005, pps. 68-69). Despite the fact that it did not sell on the New York City publishing market, Kalisha earned a 2001 Illinois Arts Council Artist Fellowship Award in Prose and an honorable mention in George Mason University's 2001 First Novel Competition, sponsored by the Mary Roberts Rhinehart Fund. The Illinois Arts Council fellowship enabled Kalisha to quit her job in order to write full-time, and she then decided to move to New York City in early 2001 to pursue an MFA in Creative Writing at The New School.

In New York, Kalisha made a home in Harlem and became a teaching artist, teaching basic grammar, literacy and language arts through such organizations as the Harlem Center for Education, Legal Outreach, The National Puerto Rican Forum and Oasis Children's Services. At The New School, she studied writing and literature under such noted writers as Hilton Als, Abigail Thomas, Zia Jaffrey and Pablo Medina. She received her first literary fiction credit with the publication of her short story "Card Parties" in the Michigan Quarterly Review. The story also won the Zora Neale Hurston/Bessie Head Fiction Award at Chicago State University's 2002 Gwendolyn Brooks Black Writer's Conference. Another of Kalisha's teachers at The New School was the bestselling, award-winning and critically-acclaimed novelist and poet Sapphire, who took Kalisha under her wing as a Black female writer struggling to make it in New York. Kalisha was preparing to work through a book of short stories for her MFA thesis, when she told Sapphire of the writings she had completed towards what was soon to be Upstate. Sapphire encouraged her to put the stories aside and pursue the novel idea more, and in less than a year Kalisha had earned her MFA in Creative Writing from The New School and finished drafting Upstate. Sapphire gave the novel to famed editor Tracy Sherrod (The Coldest Winter Ever, Addicted, much of bell hooks' work), who had just started her own literary agency (Chicago Magazine, January 2005, p. 14). After more revisions, the novel was auctioned on the New York City publishing market in a heated bidding war won by Senior Editor Monique Patterson at St. Martin's Press. Kalisha eventually earned a mid-six figure advance from St. Martin's Press for two novels, Upstate and an untitled future novel (Publisher's Weekly, December 8, 2003). In 2004, UK editor Anya Serota of John Murray Publishers in London bought Upstate for publication in Britain.

Her second novel, Conception, was released in early 2008. She explores the themes of love, heartache, hope, belief and struggle from a uniquely Black, female and lower economic class point of view. Sapphire has called her work "wild and beautiful," and Dorothy Allison noted Kalisha's work for the "power of the language." Upstate, in particular, has developed a cult following among its readers due to the "amazing amount of emotion and description" (Toronto Sun) and an opening line ("Baby, the first thing I need to know from you is do you believe I killed my father?" which "starts out strong and never lets go (Chicago Tribune)." Because her adult novels have featured young adult characters, she is a favorite in high schools and libraries across the country. In 2006, a grandmother at a high school in East Hartford, Connecticut, unsuccessfully sought to ban Kalisha's work and visit from East Hartford High School after finding the content of Upstate too objectionable for young readers.(Hartford Courant, April 16, 2006).

In 2004, Kalisha began to divide her time between New York City and Chicago in order to be closer to her family. In 2006, she planted herself full-time in Chicago to work towards a PhD in English Language and Literature at her alma mater, the University of Chicago. She earned her MA in English Language and Literature from there in December 2007. She currently resides in the Chicago neighborhood of Hyde Park.