Mandrake grew up as a fan of Marvel Comics of the 1960s, as well as painters of the Brandywine School, particularly Maxfield Parrish and Howard Pyle. Together with his friend L.B. Kellogg, he created a fanzine titled First Flight while in high school. Mandrake spent two years at Cleveland's Cooper School of Art, and then two more years at The Kubert School, where he earned his degree.
Mandrake began working for DC Comics where he drew backup stories for the Sgt. Rock title. In a 2001 interview, he recalled "finally landing my first real work, that was a two part story in DC's New Talent Showcase. Once again with my old buddy L.B. at the writers helm on our pirate epic 'Skydogs'." For Marvel Comics, Mandrake provided finished art over layouts by Sal Buscema on the New Mutants title. Back at DC, he and writer Doug Moench created the Black Mask in Batman #386 (August 1985) and the Film Freak in Batman #395 (May 1986). Mandrake was one of the contributors to the DC Challenge limited series in 1986 after finishing his run on Batman. In 1992, Mandrake and writer John Ostrander launched The Spectre series at DC Comics. In issue #54 (June 1997), the creative team introduced the character Michael Holt as a new version of Mister Terrific. Following the end of The Spectre series, they moved onto a Martian Manhunter series. In 2001, he worked with writer Dan Mishkin on the short lived series Creeps and in 2006 on the children's book The Forest King: Woodlark's Shadow. In 2007, a story-arc titled "Grotesk" reuniting Ostrander and Mandrake appeared in Batman issues 659-662. An X-Files/30 Days of Night crossover in 2010 was drawn by Mandrake and co-written by 30 Days creator Steve Niles and Adam Jones, the guitarist for the band Tool. Mandrake drew the DC Retroactive: Batman - The '70s one-shot (Sept. 2011) and a revival of Marv Wolfman's Night Force series (May–Nov. 2012). He collaborated with J. Michael Straczynski on the Sidekick series in 2013–2014.

Mandrake is married to fellow comic book artist Jan Duursema, whom he met while both were students at The Kubert School. Their wedding was held on the school's grounds. The couple have a son, Jack Moses Mandrake, and a daughter, Sian Mandrake, who is also a Kubert School-trained comics illustrator.

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