Along with his collaborator David Benioff, he is best-known for co-creating Game of Thrones (2011–2019), the HBO adaptation of George R. R. Martin's series of books A Song of Ice and Fire (published 1996-2011 for first five).

He earned a Master of Philosophy in Irish literature from Trinity College Dublin, where he wrote his thesis, "Understanding the (Net) Wake.

[4] In 2003, they were hired to collaborate on a new script based on Orson Scott Card's book Ender's Game, in consultation with the then-designated director Wolfgang Petersen.

[9] The same year, Weiss completed a screenplay for a film adaptation of the video game series Halo, based on a script by Alex Garland.

On July 19, 2017, Weiss announced that he and Benioff were going to begin production on another HBO series, Confederate, after the final season of Game of Thrones.

Weiss and Benioff said, "We have discussed Confederate for years, originally as a concept for a feature film, but our experience on Thrones has convinced us that no one provides a bigger, better storytelling canvas than HBO.

[17] On February 6, 2018, Disney announced that Weiss and Benioff would write and produce a new series of Star Wars films after the last season of Game of Thrones ended in 2019.