Over her writing career, Picoult has covered a wide range of controversial or moral issues, including abortion, the Holocaust, assisted suicide, race relations, eugenics, LGBT rights, fertility issues, religion, the death penalty, and school shootings.

Immediately after graduation, she began a variety of jobs, ranging from editing textbooks to teaching eighth-grade English.

[citation needed] Nineteen Minutes, Picoult's novel about the aftermath of a school shooting in a small town, published on March 9, 2007, was her first book to debut at number 1 on the New York Times Best Seller list.

"[4] In November 2019, Picoult participated in the criticism of Brooke Nelson, a college student who was mentioned in her local newspaper as saying she thought that author Sarah Dessen's YA novels were not suitable for the Common Read program run by Northern State University, Aberdeen, and had instead advocated for the inclusion of Just Mercy, a memoir by civil rights attorney Bryan Stevenson.

[24][25] Her 2024 novel By Any Other Name is based on the premise that the poet Emilia Lanier was the actual author of several works of William Shakespeare.

Picoult says "I think that, back then, people in theatre knew that William Shakespeare was a catch-all name for a lot of different types of authors."

[26][27][28] In 2016, Picoult joined the advisory board of VIDA: Women in Literary Arts,[29] a "non-profit feminist organization committed to creating transparency around the lack of gender parity in the literary landscape and to amplifying historically marginalized voices, including people of color; writers with disabilities; and queer, trans and gender nonconforming individuals".

[citation needed] In 2010, Picoult led the 5th Annual Children's Hospital at Dartmouth Hero Half Marathon & Relay 5K Walk around Occom Pond and through the town of Hanover, New Hampshire.

[citation needed] She was the co-founder, with Marjorie Rose, of the Trumbull Hall Troupe in 2004 as a means of providing children with a fun, educational theatre experience.

[37][38][39][40] In March 2023, 20 of Picoult's books were removed from Florida's Martin County School District for review of potentially inappropriate content.

[56] "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.