Hornschemeier was born in Cincinnati, Ohio in 1977 and raised in nearby Georgetown, Ohio. As a child he liked to draw, dreaming that he might publish his own comic books one day. While majoring in philosophy and psychology at Ohio State, Hornschemeier was introduced to the graphic novel Ghost World by Daniel Clowes and was impressed. He saw that comics could be a venue for exploring issues that are far from superficial. Following graduation he began publishing his own black and white comics. Those have been compiled by AdHouse Books under the title The Collected Sequential. He gradually began using colors in his comics, and in 2003 he published his first graphic novel titled Mother, Come Home.

In 2007 Hornschemeier colored the Marvel mini-series Omega The Unknown.

Hornschemeier is currently serializing a graphic novel called "Life with Mr. Dangerous," in the pages of Mome, published by Fantagraphics Books. He also sang and played guitar for the now defunct band Arks.