Harris was born in Tunica, Mississippi. After publishing two stand-alone mysteries, Harris began the lighthearted Aurora Teagarden books with Real Murders, a Best Novel 1990 nomination for the Agatha Awards. Harris wrote several books in the series before the mid-1990s when she began branching out into other works. She did not resume the series until 1999, with the exception of one short story in a Murder, She Wrote anthology titled, "Murder, They Wrote".

In 1996, she released the first in the Shakespeare series, set in rural Arkansas. Harris "lives in small-town Arkansas", according to a New York Times interview. The fifth book in the series, Shakespeare's Counselor, was printed in fall 2001, followed by the short story "Dead Giveaway" published in the Ellery Queen Mystery Magazine in December of the same year. Harris has stated on her website that she has finished with the series.

After Shakespeare, Harris created The Southern Vampire Mysteries series about a telepathic waitress named Sookie Stackhouse who works in a northern Louisiana bar. The first book in the series, Dead Until Dark, won the Anthony Award for Best Paperback Mystery in 2001. Each book follows Sookie as she tries to solve mysteries involving vampires, werewolves, and other supernatural creatures. The series has been released in Australia, New Zealand, Japan, Spain, Greece, Germany, the Netherlands, France, Argentina, Poland, Brazil, Great Britain, Ireland, Mexico, Norway, Finland, Sweden, Lithuania, Hungary, Bulgaria, Portugal, Iceland and Romania.

Sookie Stackhouse has proven to be so popular that Alan Ball, creator of the HBO television series Six Feet Under, announced he would undertake the production of a new HBO series based upon The Southern Vampire Mysteries. He also wrote and directed the pilot episode for the series, True Blood, which premiered on September 7, 2008 on HBO. Harris has written ten novels in the series, and the television show is a hit for HBO.

October 2005 marked the debut of Harris's new series entitled The Harper Connelly Mysteries, with the release of Grave Sight. The series is told by a young woman named Harper Connelly, who after being struck by lightning, is able to locate dead bodies and to see their last moments through the eyes of the deceased.

Professionally, Harris is a member of the Mystery Writers of America and the American Crime Writers League. She is a member of the board of Sisters in Crime, and alternates with Joan Hess as president of the Arkansas Mystery Writers Alliance.

In her personal life, Harris is married and the mother of three teenagers. A former weightlifter and karate student, she is an avid reader and cinemaphile. Harris resides in Magnolia, Arkansas, where she is the senior warden of St. James Episcopal Church.

Aurora Teagarden Series

1. Real Murders (1990)
2. A Bone to Pick (1992)
3. Three Bedrooms, One Corpse (1994)
4. The Julius House (1995)
5. Dead Over Heels (1996)
• "Deeply Dead" in Murder, They Wrote (1997)
6. A Fool And His Honey (1999)
7. Last Scene Alive (2002)
8. Poppy Done to Death (2003)

Lily Bard (Shakespeare) Series

1. Shakespeare's Landlord (1996)
2. Shakespeare's Champion (1997)
3. Shakespeare's Christmas (1998)
4. Shakespeare's Trollop (2000)
5. Shakespeare's Counselor (2001)
• "Dead Giveaway" published in Ellery Queen Mystery Magazine (December 2001)

Sookie Stackhouse (Southern Vampire) Series

1. Dead Until Dark (2001)
2. Living Dead in Dallas (March 2002)
3. Club Dead (May 2003)
4. Dead to the World (May 2004)
• "Fairy Dust" in Powers of Detection (October 2004)
• "Dancers in the Dark" a novella in Night's Edge (October 2004)
• "One Word Answer" in Bite (2005)
5. Dead as a Doornail (May 2005)
6. Definitely Dead (May 2006)
• "Tacky" in My Big, Fat Supernatural Wedding (2006)
7. All Together Dead (May 2007)
• "Dracula Night" in Many Bloody Returns (September 2007)
• "Lucky" in Unusual Suspects (December 2008)
8. From Dead to Worse (May 2008)
• "Gift Wrap" in Wolfsbane and Mistletoe (October 2008)
• "Bacon" in Strange Brew (July 2009)...also makes an offhand reference to Jim Butcher's wizard, Harry Dresden;
9. Dead and Gone (May 2009)
• "The Britlingens Go To Hell" in Must Love Hellhounds (September 2009)
• A Touch of Dead (October 2009)...a compilation of all the Sookie-centric short stories
• "Dahlia Underground" in Crimes by Moonlight (April 2010)...takes place during All Together Dead
10. Dead in the Family (May 2010)
• "Two Blondes" in Death's Excellent Vacation (August 2010)
• The Sookie Stackhouse Companion (February 2011)...a new novella, interviews, FAQ, recipes, and more

Harper Connelly Series

1. Grave Sight (2005)
2. Grave Surprise (2006)
3. An Ice Cold Grave (2007)
4. Grave Secret (2009)

Other/non-series

• Sweet and Deadly (1981) republished in UK as Dead Dog
• A Secret Rage (1984)
• "An Evening With Al Gore" in Blood Lite (October 2008)

As editor

• Many Bloody Returns (September 2007) (co-editor with Toni LP Kelner)
• Wolfsbane and Mistletoe (October 2008) (co-editor with Toni LP Kelner)
• Crimes by Moonlight (April 2010)
• Death's Excellent Vacation (expected August 2010) (co-editor with Toni LP Kelner)