He is best known for creating, writing, and producing the HBO historical disaster drama miniseries Chernobyl (2019) and co-creating, co-writing, and executive producing the HBO post-apocalyptic drama series The Last of Us (2023–present), the latter alongside Neil Druckmann.

His roommate during his freshman year was future Republican politician Ted Cruz, whom he now often describes as a "huge asshole".

[5][6][7] Mazin began his entertainment career as a marketing executive with Walt Disney Pictures in the mid-1990s, where he was responsible for writing and producing campaigns for studio films.

[4] He made his screenwriting debut with 1997's sci-fi comedy RocketMan, co-written with his then-writing partner Greg Erb.

Along with fellow former WGA board member Ted Elliott, Mazin ran a website called The Artful Writer, which focused on issues relevant to working screenwriters.

[11] In an interview with Decider, he said, "If I came to HBO and said 'I want to do another season of Chernobyl, except it's gonna be about another tragedy,' whether it's Bhopal or Fukushima or something like that, I would imagine they at least would give me polite interest.