She has written ten novels for teens and young people, including Infinite in Between; Not If I Can Help It; The Earth, My Butt, and Other Big Round Things, which won an honorable mention from the Michael L. Printz award;[1] Vegan Virgin Valentine; Guyaholic; and Tangled.

Her first novel for adults, The Wife App, received praise from authors such as Judy Blume and Gabrielle Zevin.

Her second novel The Earth, My Butt, and Other Big Round Things was released in 2003, the year Mackler and her husband married.

The Earth, My Butt, and Other Big Round Things was one of the top 10 most challenged books in 2009 as reported to the Office for Intellectual Freedom.

In 2011, Mackler and Jay Asher, co-authored The Future of Us, which received starred reviews and landed on several bestseller lists.

Infinite in Between received starred reviews from Publishers Weekly, Kirkus, School Library Journal, and VOYA.

[7] Mackler was a self-proclaimed misfit in junior high; she never felt she completely fit in, and this has been a determining factor in her deciding to write young adult novels.