Set in Hollywood of the 1950s, the film starts with Eddie Mannix (Josh Brolin) going to confession at a local church. The priest is already used to hearing from Eddie too often. Eddie confesses that he has been hiding his smoking habit from his wife.
Eddie drives to a house where a young actress, Gloria DeLamour (Natasha Bassett), is doing a photoshoot while wearing provocative clothing. Eddie has called the cops to get the photographer and then slaps Gloria twice before giving her an alias to protect her image and an alibi.
Eddie is revealed to be a fixer for the studio Capitol Pictures, keeping the reputations of the studio's actors safe. He watches a rough cut of "Hail, Caesar!", a historical epic centered around The Christ. Famous actor Baird Whitlock (George Clooney) stars in the lead role of Autolycus. Eddie is seen consulting with a rabbi, Protestant clergyman, Catholic clergyman, and Eastern Orthodox clergyman to discuss the portrayal of Jesus Christ being done properly without offending anyone's views, leading to a debate on the role of Jesus in each religion.
In addition to "Hail, Caesar!", Eddie is also involved in the production of a Broadway adaptation called "Merrily We Dance". He gets popular Western star Hobie Doyle (Alden Ehrenreich). We see Hobie performing in a Western film, pulling off cool stunts against the bad guys. When Hobie is brought in to act for "Merrily We Dance", he meets the director, Laurence Laurentz (Ralph Fiennes). The cameras roll, and Hobie is unable to pull off a convincing British accent with his heavy Southern drawl. Laurentz tries to get Hobie to say the line "Would that it were so simple" repeatedly, but he never quite gets it right, leading Laurentz to go complain to Eddie.
During the filming of "Hail, Caesar!", an extra (Wayne Knight) pours a powdered substance into a goblet that Baird is supposed to drink out of. Baird shoots the scene and drinks from it. Later, as he walks to his dressing room, the extra and his cohort (Jeff Lewis) follow Baird and catch him as he passes out, and they abduct him.
Another issue Eddie has to deal with is actress DeeAnna Moran (Scarlett Johansson). She is introduced doing a mermaid water sequence with a big smile before experiencing discomfort and tossing her crown to someone violently. DeeAnna is pregnant, which spells trouble for her generally wholesome image.
Baird wakes up in a house by the beach and walks into a meeting of men gathered in a room. Baird sits with them and learns that they are all communist writers that felt cheated by the studios, and they want Baird to join them in their cause.
People notice that Baird has gone missing. Eddie receives a message demanding a ransom of $100,000 for Baird's return, issued by "The Future". As Eddie tries to manage the situation, he is hounded by columnist Thora Thacker (Tilda Swinton) over a story about Baird regarding a film he did years earlier called "On Wings With Eagles." Not long after Thora leaves, Eddie is approached by her twin sister Thessaly, who writes gossip pieces and also wants to do a piece on Baird. A young man on a bike approaches Eddie and says he has a call from "The Future." Eddie runs to his office to answer the call, but they hang up on him. Hobie is already waiting for him in his office. Eddie shows him a suitcase full of the ransom money and explains the situation to Hobie.
Meanwhile, Eddie is pursued by a man from Lockheed Martin to leave Hollywood behind and go work for him.
We meet actor Burt Gurney (Channing Tatum) in a musical as a sailor who sings with his comrades over seeing "no dames" for the next eight months at sea.
Eddie visits C.C. Calhoun (Frances McDormand), who is the editor of "Merrily We Dance". He catches a glimpse of footage from the film. Before it gets to Hobie's part, the reel stops because C.C.'s scarf gets caught in the projector and is choking her. Eddie reverses the reel and saves her.
Eddie approaches Arne Seslum (Christopher Lambert), the director with whom DeeAnna had an affair with and fathered her child. He tells Eddie he is married. Eddie resolves to have DeeAnna disappear for a while and "adopt" her own child to hide that it's really hers. They find Joe Silverman (Jonah Hill), a fall guy that has previously been used as a scapegoat to fix someone else's problem. They arrange for Joe to be the foster father to DeeAnna's baby.
Hobie is set up with actress Carlotta Valdez (Veronica Osorio) to accompany each other to the premiere of Hobie's movie "Lazy Ol' Moon". The film is a laugh-out-loud riot for the audience. After the movie, Hobie and Carlotta have dinner together as part of the studio's plan to make them look "sweet on each other." Hobie is approached by both Thacker sisters individually to get the scoop on the two of them. From a few tables down, Hobie notices Burt taking the suitcase of money with him. Hobie leaves Carlotta and follows Burt.
Hobie follows Burt all the way to the beach house where he finds Baird sitting alone in the meeting room. Baird tries to convince Hobie to join The Future, but he refuses to be a communist and takes Baird with him. Meanwhile, the writers are taking Burt (who is also a communist) to the middle of the ocean where a Soviet submarine rises from the water. Burt takes the suitcase with him as he boards the submarine, but a small dog on the little boat hops over, prompting Burt to catch the dog and drop the suitcase into the water. He boards the submarine, which goes back underwater. As Hobie drives Baird away, the police make their way to the beach house to arrest the writers.
When Baird returns, he plans to smear the name of the studio head as The Future would have wanted, but Eddie smacks him twice and tells him to proceed with "Hail, Caesar!" and to not even think about ruining the reputation of the man that made him famous. Baird is then seen performing a monologue in the film as they see Jesus on the cross. The speech is powerfully spoken until Baird forgets one of his lines.
Eddie is approached by Thora again in regards to the "On Wings With Eagles" story. Apparently, Baird got the part in that movie by sleeping with Laurentz, but because her source was Burt, Eddie tells her that she would be branded a communist if she were to run that story. Eddie is then approached by his secretary and is told that DeeAnna and Joe met up for dinner and later eloped.
In the final scene, Eddie goes to confession one more time. The priest tells him he's not so bad if he comes by too often. He also tells Eddie that God wants everyone to do what is right. This inspires Eddie to stay with Capitol Pictures and continue takfing pride in his job.