Metzen began his career working with art and animation. He applied to Blizzard Entertainment, then known as Silicon & Synapse, on the recommendation of a friend who had seen his work. He was quickly recruited by the company, although Metzen states that at the time he did not really know what Blizzard Entertainment dealt with, assuming it was a graphic design studio rather than a video game developer.

Metzen's first work for the company was with the game Justice League Task Force, in which he provided artwork and character animation. Around the same time, Metzen also contributed to 1994's Orcs and Humans by working on artwork, illustrations and the game's documentation. Later video games by Blizzard Entertainment would frequently include Metzen's work in manual design, illustration and concept art. However, Metzen's role in developing later Warcraft games increased significantly with 1995's Tides of Darkness, which gave him the opportunity to work on the game's fantasy-based fictional universe in addition to designing the game's various scenarios and missions.

In 1997, Blizzard Entertainment launched its second major franchise with the role-playing game Diablo. Diablos fictional universe was created by both Metzen and fellow designer Bill Roper, and Metzen also provided voice acting for some of the game's characters. On occasion, Metzen would provide voice talent for later video games. In 1998 he took the role of lead designer on the science fiction strategy game StarCraft. Along with James Phinney, Metzen again provided the game's extensive story and script, as well as organizing the voice casting for the game. In 1999, Metzen wrote a short story set in the StarCraft universe with fellow Blizzard Entertainment employee Sam Moore. The story, entitled Revelations, was published in the spring issue of Amazing Stories with cover artwork by Samwise Didier. Returning to the Diablo series in 2000 with Diablo II, Metzen worked on the game's story, script and artwork. In 2001, he published a novel set in the Warcraft universe, entitled Of Blood and Honor.

With 2002's Reign of Chaos, Metzen was the creative director, a role he would hold in all of Blizzard's later video games, and provided the game's story concept and script. Metzen's work with 2004's massively multiplayer online role-playing game World of Warcraft was not as extensive as his earlier work, but he still contributed with script writing, artwork and voice work.

Metzen announced in early 2005 that he was working on graphic novel series independent of Blizzard Entertainment. The series, entitled Soldier: 76, is set in a second American civil war in 2010, with increased domestic and global terror threats and the increase in power for the US federal government over that of local state governments serving as a background. Metzen wrote the series' script, while Brazilian artist Max Velati was responsible for the illustration and painting of the book.

Metzen describes himself as a "comic book geek", stating that he first started creating comics at the age of twelve, but that he had held an interest in drawing since at least six. He states that he still retains a habit of spending "an average thirty-five dollars per week" on comics books. A fan of Dungeons & Dragons, Metzen cites the Dragonlance series of novels and Star Wars as the primary inspirations for his fantasy and science fiction creations, and names fantasy and comic book artists such as Walt Simonson and Keith Parkinson as his artistic inspirations. He defines his artistic style as having been "heavily influenced by Walt Simonson's and Jim Lee's pencilling styles for form" while preferring the "costuming, themes and general feel of Larry Elmore and Keith Parkinson's fantasy paintings". In addition to art, Metzen's interests include pop and rock music, the nightlife, and dirt bikes. Metzen has a daughter, Sofia, who was born in 2003 and a son, Lucas, born in 2008. He and his wife, April, reside in Santa Ana, CA.