The fourth season continues the Medellin plotline as production of the film finally begins. Conflicts quickly arise when E admits to being dissatisfied with the first cut after Walsh reluctantly agrees to a midnight screening. Vince and E subsequently clash over the creative direction and financing of the film in an arc which escalates through the season.
When the Medellin trailer leaks to the public via YouTube, an opportunity is presented to leverage the resultant hype to broker a deal attaching Vince to a new big-budget project. The deal, however, is unexpectedly sold on the strength of not just Vince, but the "Medellin Dream Team" — also involving E as producer and Walsh as director — at the point when animosity between E and Walsh begins to come to a head. Consequently, E must decide between jeopardizing the deal, and the prospect of working on another project with Walsh, which he had previously sworn he would never do again. There is much contention over the ending of the script, and Stephen Gaghan is brought in briefly, at which point Walsh comes up with what he believes to be a good ending.
Meanwhile, Ari contends with various complications in his personal and professional lives, including the incapacitating relationship troubles of his indispensable assistant, Lloyd, the uncertainty of his son's acceptance into the exclusive private school his daughter currently attends, and interpersonal conflicts between employees of his agency.
E navigates unfamiliar waters as he clumsily attempts to expand the representation of his fledgling management agency beyond Vince, his only client at the time. By chance he comes to meet and subsequently represent Anna Faris, but when his loyalty to Vince and his personal feelings for Faris are set at odds with one another and compromise his professional judgement, he is ultimately fired by Faris.
Drama and Turtle are featured throughout the season in various subplots that see them engaging in the type of antics typical of their characters, such as procuring marijuana and engaging in furry fetishes via Craigslist on a bet.
In the season finale, the entourage travel to Cannes to promote Medellin, and sign a distribution deal. However, the film bombs with the Cannes audience, and they are forced to accept an offer from producer Harvey Weingard (whom they earlier rebuffed) of a mere one dollar for the movie.