DeCandido worked as editor at several publishing companies. Along with John Drew, in the 1990s he co-produced a public-access television cable TV show in Manhattan about science fiction called The Chronic Rift, which he also co-hosted. DeCandido and Drew and others revived the show as a podcast in 2008. DeCandido also hosts his own monthly podcast, Dead Kitchen Radio.
While DeCandido spent much of his career writing Star Trek fiction, he has written tie-ins for other popular sci-fi and fantasy series as well, such as Buffy the Vampire Slayer, Doctor Who, Supernatural, Stargate SG-1, Sleepy Hollow, Farscape, and Leverage as well as comic books (Spider-Man, X-Men), movies (Cars, Serenity), role-playing games (Dungeons & Dragons), and video games (World of Warcraft, StarCraft, Command & Conquer). He has also written fiction in universes of his own creation, including that of the 2004 novel Dragon Precinct, a high-fantasy police procedural, and a series of short stories about Cassie Zukav, a scuba diving tour guide in Key West who learns she is a Dis.
Other worlds of DeCandido's own creation include the Bram Gold Chronicles and the Super City Cops series. He has also edited various anthologies, including OtherWere, Urban Nightmares, Imaginings, the Doctor Who collection Short Trips: The Quality of Leadership, and the Star Trek anthologies New Frontier: No Limits, Tales of the Dominion War, and Tales from the Captain's Table. In 2009, DeCandido was named Grandmaster by the International Association of Media Tie-In Writers.
He has completed a Star Trek: The Next Generation Rewatch, a Star Trek: Deep Space Nine Rewatch, and a Stargate Seasonal Rewatch for Tor.com, and is now writing an Star Trek: The Original Series Rewatch and a Batman, rewatch for the same site.