Meltzer grew up in Brooklyn, N.Y., and then moved to South Florida, where he graduated from North Miami Beach Senior High School in 1988. He then obtained a degree from the University of Michigan, the first in his immediate family to attend a four-year college. In 1993, Meltzer lived in Beacon Hill, Boston, Massachusetts with roommate, fellow comic book writer/artist Judd Winick, working in sales at Games Magazine by day while working on his first novel by night. Afterwards Meltzer attended Columbia Law School, from which he graduated and was selected to the prestigious Columbia Law Review.

According to his website, his first novel Fraternity got 24 rejection letters but he then sold The Tenth Justice (which is really his second novel) while in law school.

In 1994, he co-wrote the original swearing-in oath that is taken by all AmeriCorps members, and has been delivered by Presidents Bill Clinton and George W. Bush.

In addition to his novels, he was the co-creator of the television series Jack & Bobby, which ran for one season (2004-2005) on the WB television network.

He created a six-issue story arc for DC Comics' Green Arrow #16 - #21 (October 2002 - April 2003), and the 2004 miniseries Identity Crisis. He took over the writing duties for a 13-issue stint on the new monthly Justice League of America series, which started with issue #0 on July 19, 2006. Issue #1 following a month later. Meltzer and artist Gene Ha received the 2008 "Best Single Issue (or One-Shot)" Eisner Award for their work on issue 11 of the series. The award was presented by Samuel L Jackson.

In September 2006, Meltzer participated in a work group along with the CIA, FBI, various psychologists, and Department of Homeland Security intelligence staff to brainstorm new ways that terrorists might attack the U.S.

In 2008, it was announced that Meltzer would write an arc of Joss Whedon's Buffy the Vampire Slayer Season Eight comic book for Dark Horse Comics. Whedon would later star as himself, alongside Brian K. Vaughan and Damon Lindelof in the trailer for Meltzer's 2008 release of The Book of Lies. Whedon, Vaughan and Lindelof - who portray themselves - act as conspiracy theorists who believe in a so-called "Book of Lies", which in Meltzer's novel connects the original murder story (Cain and Abel) to the murder of Jerry Siegel's father, shortly before the conception of the iconic Superman character. In 2010, Meltzer wrote #32 - #35 of Buffy the Vampire Slayer Season Eight.

In May 2010, Meltzer release his first ever nonfiction book, Heroes For My Son, a book he'd been working on for almost a decade, since the night his first son was conceived.  The book is a collection of heroes, from Jim Henson to Rosa Parks to Mr. Rogers, and was written for his two sons, Ice and Seltzer.  It was a surprise bestseller and debuted at #2 on the New York Times bestseller list.

In 2010, he will host the History Channel series, "Brad Meltzer Decoded."