Horowitz was born to a Jewish family, and graduated from Hunter College High School in 1990. He attended University of Wisconsin–Madison and graduated with a B.A. in 1994, majoring in communication arts and political science. There he met his Future collaborator, Edward Kitsis. Horowitz was Writer and reporter for the Daily Cardinal student newspaper, writing as many as five articles in the same issue. He often caught editors off-guard with humorous leads or picking odd quotes. He worked on articles about spearfishing and the Exxon Valdez oil spill.

Horowitz, Kitsis and the Lost writing staff won the Writers Guild of America (WGA) Award for Best Dramatic Series at the February 2006 ceremony for their work on the first and second seasons. They were nominated for the WGA Award for Best Dramatic Series again at the February 2007 ceremony for their work on the second and third seasons, at the February 2009 ceremony for the fourth season of Lost and at the February 2010 ceremony for the fifth season. They also wrote Confessions of an American Bride, a made-for-television movie.

Kitsis and Horowitz worked as Writers on early unused drafts of the Universal project Ouija, and co-wrote the film Tron: Legacy in 2010.

Horowitz and Kitsis created the ABC fantasy drama series Once Upon a Time, which began airing on October 23, 2011. The show focuses on a town which is actually a parallel world populated by fairytale characters who are unaware of their true identity. The two came up with the concept seven years prior to joining the staff of Lost, but wanted to wait until it ended before they focused on this project.