Mazin graduated magna cum laude with a degree in psychology from Princeton University in 1992. His freshman-year roommate at Princeton was Ted Cruz, now the junior U.S. Senator from Texas and a former Republican candidate for the 2016 presidential election year. He is highly critical of Cruz as well as his political views, and ridicules him frequently on Twitter.

In 2004, Mazin was elected to the board of directors of the Writers Guild of America, West. He did not seek re-election, and his term expired in September 2006.

Since 2006, Mazin has collaborated with director Todd Phillips on several occasions. Mazin co-wrote both Hangover sequels, parts II and III, and executive produced School for Scoundrels.

Mazin was born in Brooklyn, New York, to a Jewish family. He was raised on Staten Island, New York. He moved to Marlboro Township, New Jersey when he was a teen and attended Freehold High School which inducted him into its Hall of Fame in 2010.

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. It closed in 2011, after seven years.

In 2011, Mazin and fellow screenwriter John August began Scriptnotes, a weekly podcast on the craft of screenwriting and the film industry.

In July 2017, HBO and Sky Television announced Chernobyl, a five-part miniseries from Mazin about the nuclear disaster at Chernobyl. The series was filmed in Lithuania and Ukraine. Mazin said that the “lesson of Chernobyl isn’t that modern nuclear power is dangerous. The lesson is that lying, arrogance, and suppression of criticism are dangerous.”

Mazin was named as the current scriptwriter for the Lionsgate film adaption of the Borderlands video game series in February 2020, as well as co-writer and co-executive producer for a television series adaption of the video game The Last of Us for HBO in March 2020.