McCafferty hails from Bayville, New Jersey, and moved to Brooklyn and Manhattan before settling in Princeton, New Jersey. She graduated from Central Regional High School in Berkeley Township, New Jersey in 1991. McCafferty attended the University of Richmond before transferring to Columbia University to earn a bachelor's degree in English. After graduation, McCafferty worked in magazine publishing as an editor for Cosmopolitan, YM, and Fitness magazines. She began her writing career with writing short stories and articles for various teen magazines.

McCafferty's first novel, Sloppy Firsts, was published on August 28, 2001. Told from the diary-style perspective of character Jessica Darling herself, the series chronicles her misadventures through high school, college, and beyond. McCafferty subsequently published Second Helpings on April 22, 2003. This was later followed by Charmed Thirds (April 11, 2006), Fourth Comings (August 7, 2007), and Perfect Fifths (April 14, 2009). Perfect Fifths, the fifth and final Jessica Darling novel, is the only book in the series told in third person from the alternating perspectives of Jessica Darling and her long-time love, Marcus Flutie. The third, fourth and fifth books all made the New York Times Best Seller List.

McCafferty also published a Jessica Darling short story called "Fifteen Going On ..." in a May 25, 2004 anthology called Sixteen: Stories About That Sweet and Bitter Birthday, which she also edited.)

In 2006, Harvard student and novelist Kaavya Viswanathan was accused of plagiarizing the work of McCafferty and other writers in her novel How Opal Mehta Got Kissed, Got Wild, and Got a Life.

McCafferty has also contributed to several fiction and nonfiction anthologies. Her work has been translated into eleven languages including Bulgarian, Chinese and German and has been awarded numerous honors by such associations as the American Library Association and the New York Public Library.

McCafferty keeps what she terms a "retro(blog)" in which she posts actual journal entries and creative writing from her adolescence, which can be found at her website.

1. Girls' Night In, edited by Lauren Henderson, Chris Manby and Sarah Mlynowski
2. It's a Wonderful Lie: 26 Truths About Life in Your Twenties, edited by Emily Franklin
3. Everything I Needed To Know About Being a Girl I Learned From Judy Blume, edited by Jennifer O'Connell
4. If I'd Known Then: Women in Their 20s and 30s Write Letters to Their Younger Selves, edited by Ellyn Spragins
5. A New Dawn: Your Favorite Authors on Stephenie Meyer's Twilight Series, edited by Ellen Hopkins
6. Does This Book Make Me Look Fat? Stories about loving...and loathing...your body, edited by Marissa Walsh
7. My Little Red Book, edited by Rachel Kauder Nalebuff