Picoult was born and raised in Nesconset on Long Island, and moved to New Hampshire when she was 13 years old. She has described her family as "non-practicing Jewish". Picoult wrote her first story at age 5, entitled "The Lobster Which Misunderstood". She studied writing at Princeton University, and graduated in 1987. She published two short stories in Seventeen magazine while still in college. Immediately after graduation, she landed a variety of jobs, ranging from editing textbooks to teaching eighth-grade English. She earned a master's degree in education from Harvard University.

Picoult became the writer of DC Comics' Wonder Woman (vol. 3) series following the departure of fellow writer Allan Heinberg. Her first issue (#6) was released on March 28, 2007, and her last was issue #10 (released on June 27, 2007).

Nineteen Minutes, Picoult's novel about the aftermath of a school shooting in a small town, has become her first book to debut at #1 on the New York Times Best Seller list. Her book Change Of Heart was published on March 4, 2008, and became Picoult's second novel to debut at #1 on the NYT Best Seller list.

She is married to Tim Van Leer, whom she met while in college. They and their three children, Sammy, Kyle, and Jake, and a handful of pets, live in Hanover, New Hampshire.

• Jordan McAfee, his son Thomas, and his wife Selena are featured in The Pact, Salem Falls and Nineteen Minutes.
• Patrick Ducharme, a detective, is featured in Perfect Match as well as Nineteen Minutes. She has stated that she brought Patrick's character back for a second novel because she has a crush on him.
• Ian Fletcher of Keeping Faith makes a brief appearance in Change of Heart, published in 2008.
• Frankie Martine, first featured in Salem Falls, returns in Second Glance, and Perfect Match.
• Nina Frost, a main character in Perfect Match, is mentioned in Nineteen Minutes.
• Peter Houghton, a main character in Nineteen Minutes, is mentioned briefly in House Rules.

"It’s always great fun to bring a character back, because you get to catch up on his/her life; and you don’t have to reinvent the wheel—you already know how he speaks, acts, thinks."