Trigiani grew up in Big Stone Gap, Virginia and attended Saint Mary's College in Notre Dame, Indiana. She was a writer for The Cosby Show and its spin-off series A Different World before beginning on novels. In 1996, she won the "Most Popular Documentary" award at the Hamptons International Film Festival for directing the Queens of the Big Time. The following year, she served as co-producer on the documentary film Green Chimneys.
In 2001, Trigiani wrote a novel about the town titled Big Stone Gap. It was followed by three sequels, Big Cherry Holler,Milk Glass Moon, and Home to Big Stone Gap. Aside from that series, she has written Rococo, Queen of the Big Time, and Lucia, Lucia. She also co-wrote a cookbook with her sisters, appropriately titled Cooking With My Sisters: One Hundred Years of Family Recipes, from Bari to Big Stone Gap. Trigiani's latest novel, Very Valentine, was published in February 2009.