At the age of two,[2] she and her family moved to Evanston, Illinois, and she has since spent the majority of her life living in or close to Chicago.

Niffenegger completed her undergraduate degree at the Art Institute of Chicago where she worked on becoming a visual artist.

[5] Niffenegger is also the founding member of T3 or Text 3, an artist and writer's group which performs and exhibits in Chicago.

[11] In March 2009, Niffenegger sold her second novel, a literary ghost story called Her Fearful Symmetry, to Charles Scribner's Sons for an advance of $5 million.

[14] Though not as huge a commercial juggernaut as The Time Traveler's Wife, this book generally garnered more positive critical reviews and cinched Niffenegger's reputation as a leading novelist of ideas and atmosphere.

[15] Niffenegger collaborated with Wayne McGregor on a balletic fable, Raven Girl (2013), performed at the Royal Opera House in London in 2013, 2015.

Niffenegger and Campbell collaborated on the visual novel Bizarre Romance to celebrate the Comics Unmasked exhibit at the British Library.

[23] Niffenegger describes herself as "somewhere in the spectrum of agnosticism and atheism" and ascribes her disbelief to her Catholic background.