Weiner was born in 1965 in Baltimore, to a Jewish family. He attended The Park School of Baltimore and grew up in Los Angeles where he attended Harvard School for Boys. His father was a medical researcher and chair of the neurology department at University of Southern California. His mother graduated from law school but never practiced. He enrolled in the College of Letters at Wesleyan University, studying literature, philosophy, and history and earned an MFA from the University of Southern California School of Cinema and Television.

Weiner described the start of his career as a "dark time. Show Business looked so impenetrable that I eventually stopped writing." During this time, his wife financially supported them with her work as an Architect. He began his screenwriting career writing for the short-lived Fox sitcom Party Girl (1996). He was a Writer and Producer on The Naked Truth and Andy Richter Controls the Universe. Weiner wrote the pilot of Mad Men in 1999 as a spec script while working as a Writer on Becker. The Sopranos creator and executive Producer David Chase offered Weiner a job as a Writer for the series after being impressed by the script.

Weiner also spent the hiatus between the two seasons teaching at his alma mater, the University of Southern California School of Cinema-Television (now School of Cinematic Arts), where he taught an undergraduate screenwriting class on Feature Rewriting during the Fall 2004 semester.

During his time on The Sopranos Weiner began looking for a network to produce Mad Men. HBO, Showtime and FX passed on the project. HBO offered to produce the series if Chase would be on board as a Writer or Producer, but Chase instead chose to focus on developing feature films. Weiner eventually pitched the series to AMC, which had never produced an original dramatic television series. They picked up the show, ordering a full 13-episode season. Mad Men premiered on July 19, 2007, six weeks after The Sopranos concluded. Weiner served as showrunner, an executive Producer, and head Writer of Mad Men throughout its seven seasons. As the showrunner he has had a major role in the writing and directing of each episode, also approving actors, costumes, hairstyles, and props. He is credited with writing or co-writing seven episodes of the first season, eleven episodes of the second, twelve episodes of the third, ten of the fourth, nine of the fifth, ten of the sixth, and twelve of the seventh. He has also directed all seven season finales, along with the season seven midseason finale and the penultimate episode of the series.

Weiner and his writing staff also won a Writers Guild of America Award for Best New Series and were nominated for the award Best Dramatic Series at the February 2008 ceremony for their work on the first season. They were nominated for the WGA award for Best Dramatic Series a second time at the February 2009 ceremony for their work on the second season. Weiner and the writing staff won the WGA Award for Best Drama Series (after being nominated for the third consecutive year) at the February 2010 ceremony for their work on the third season. Weiner was also twice nominated for the WGA award for episodic drama at the February 2010 ceremony for his work on "The Grown-Ups" (with co-writer Brett Johnson) and "Guy Walks into an Advertising Agency" (with Robin Veith).

Weiner's first feature film, Are You Here, filmed in North Carolina, premiered at the 2013 Toronto International Film Festival and was released in 2014.

On November 9, 2017, former Mad Men Writer Kater Gordon accused Weiner of telling her at the office one night that she owed it to him “to see her naked.” Gordon never formally complained, saying it was for fear of hurting her career. The comment shook her, and within a season she never worked in TV again. She decided to speak out years later after allegations of sexual misconduct by Louis C.K. and allegations of others of sexual assaults in Hollywood came to light, saying it provided her a safe space to reveal her allegation. Weiner denied the allegation.