The film begins with an image of an old vinyl playing "the longest-running radio play in history." Indistinguishable filtered voices can be heard in the recording.Eventually the scene fades into what appears to be a dimly lit hotel hall, where a man and a woman, both of whose faces are blurred beyond any recognition, stumble into a hotel room. Speaking Polish, the man asks the woman to undress, which she does reluctantly. As she does this, the man asks her if she knows what whores do, to which she replies "they fuck." Presumably the woman is herself a prostitute.Next, in another hotel room, a raven-haired woman, known only as the Lost Girl (Karolina Gruszka) sits crying while watching a television.On the television is an eerie sitcom about a family of rabbit-people in a small room who speak in terse, seemingly meaningless sentences, that are occasionally followed by a non-sequitur laugh-track. The female rabbit talks about a "secret" that apparently the male rabbit knows about. A knock at the door transpires. All three rabbits are captivated by it, and the male rabbit goes to answer it, but the knocker is not revealed. He walks out through the door and it closes behind him.The Male Rabbit enters a dimly lit room, which then fades into a lavish golden room where a bald man sits on a couch. Another gruff-looking Polish man stands talking to him. The seated man talks about seeking an opening, and the standing man juggles variations of the phrase "do you understand?"The scene changes. An old woman with bulging eyes (Grace Zabriskie), walks down a suburban neighborhood, looking dizzy. She steps onto the porch of a lavish mansion and when a butler answers, she introduces herself as a "new neighbor" who would like to greet the homeowner. The house belongs to Nikki Grace (Laura Dern), a well-known actress, and she invites the old woman in. The neighbor says that she heard Nikki got a new part for a film called On High in Blue Tomorrows. Nikki tells her it isn't for certain since the audition took place very recently, but the woman insists she has gotten it. The neighbor then talks about a boy who opened a door and saw the world, thus creating a reflection that caused evil to be born. She adds "a variation" of the tale, about a girl who got lost in an alley behind a marketplace, and then remembered something. The woman then asks if there's a murder in the movie for which Nikki auditioned. Nikki says no. Nikki, increasingly confused and unsettled by the woman's manner, asks her to leave. Ignoring Nikki, the neighbor explains that she has trouble keeping track of time: yesterdays, todays, and tomorrows. She remarks that it may be 9:45 a.m. when it is in fact after midnight. The neighbor points across the room and says that, if it were tomorrow, Nikki would be over there. Time shifts and we see Nikki, now sitting where the woman indicated, receive news via telephone that she's won the audition.An indefinite time after she hears that she has gotten the part for the film, Nikki appears with her co-star, Devon Berk (Justin Theroux) on "The Marilyn Levins Show", a talk show akin to "The View" and other celebrity programs. Marilyn asks both actors whether or not they will have an on-set affair, to which both Nikki and Devon respond negatively. Afterwards, Devon is told by his entourage that Nikki is "hands-off," since Nikki's husband is an extremely influential and powerful figure.Afterwards on a studio soundstage, Nikki and Devon prepare to read through the script with their director, Kingsley Stewart (Jeremy Irons) and his assistant Freddie Howard (Harold Dean Stanton). Later, while they rehearse a scene, there is a disturbance somewhere in the set. Devon goes to investigate the noise, but doesn't find anything. Kingsley chooses the tense moment to disclose, reluctantly, that On High in Blue Tomorrows is in fact a remake of an older unfinished Polish film called 47, which was abandoned since it was rumored that it was cursed. Kingsley nervously assures them both that nothing will come of it.At this point, Nikki's world begins to blend with that of the film they are making, putting into question whether or not the alleged "curse" is in fact real.A woman with severe stomach wounds (Julia Ormond) tells a cop she is going to kill someone with a screwdriver. This actress will later reappear as the wife of Billy Side, a character in Nikki's film.In early 20th Century Poland, prostitutes confront various pimps while murder permeates their city.In present-day Poland, a mafia-like organization discusses one of their captives, remarking that the man claimed he was from "Inland Empire."One day off the set, Nikki is shopping for groceries when she sees "Axx o Nn," chalked onto a wall with an arrow pointing to a door. She passes through the door and enters a movie studio. She hears voices and begins running. She looks back: she sees herself, Devon, Kingsley and Freddie from the scene earlier in the movie when they heard a strange noise. Devon comes along to investigate just as he did before. Susan realizes that SHE was in fact the intruder, and that she had heard herself sneak into the studio. Nikki evades exposure by hiding behind the facade of the house in the movie where her character lives. When she crosses the threshold, it miraculously metamorphoses into an actual house somewhere in the suburbs. Nikki sees it is filled with prostitutes who are having a surreal party, and dancing to 60's music. She listens to their stories, smoking and donning their suggestive garb, eventually becoming one herself.It slowly turns out that Nikki is in fact Susan Blue, the character that she portrays in the movie, who lives in a suburban home with her husband Smithy. Nikki (now called Susan) is at a backyard party with her husband and several of his circus troupe associates. She sees two of the prostitutes from earlier scenes seated on the grass some distance away and addresses a question to them that they asked her earlier in the movie: "look at me, and tell me if you've seen me before." Susan wanders into a backyard dressed in a business suit and finds a man with a light bulb in his mouth. Frightened, she brandishes a screwdriver at him, and runs away.Susan runs down Hollywood Boulevard, attempting to flee the woman with the screwdriver who is now stalking her. Wandering the streets bloody and lost while attempting to escape the treacherous woman, Susan hides in a nightclub, where she meets in a back room with a fat man with glasses known only as Mr. K (Erik Crary). She begins an epic and foul-mouthed monologue in which she unloads all her childhood scars, including being molested as a girl, when she gouged out the eye of her rapist.Susan leaves the nightclub and runs down the street where the woman stabs her with the screwdriver and leaves her for dead. Susan wanders over to a closed down storefront where she collapses to the ground, coughing up blood and sees three homeless people-- a black man (Terry Crews), a woman missing half of her teeth, and a young Japanese woman-- staring at her. The Japanese woman, speaking with an almost unintelligibly thick accent, rambles on to Susan and her street friends about her drug addicted friend Nico who lives in Pomona with her pet monkey. Susan then dies, and.... Kingsley yells "Cut!" The entire event is revealed to be the movie's final scene shot, and the street people are actors who walk off the set.Susan, now turned back to Nikki, leaves the set and wanders through the streets to an old hotel where, down a dark corridor, she finally confronts the standing man from earlier in the film, known now as "The Phantom." She shoots him, which causes his face to become hideously disfigured, at first becoming a disturbing copy of Nikki's own face, but eventually morphing into something closely resembling a fetus. We next go to the rabbits again, who are once more faced with the opened door.Nikki then goes to the hotel room where the Lost Girl is being held, opens the door and with a bright light and kiss from Nikki, the Lost Girl is freed from her prison and disappears, as does Nikki. The Lost Girl returns to her home in the suburban San Fernando Valley where she is the real Susan Blue and she is reunited with her husband Smithy and her young son who are happy to be back together at last. Nikki reappears in the mansion where she was first introduced, calm and smiling once more.The film ends in a hotel lobby as the group of prostitutes join another group of women in dancing to Nina Simone's "Sinnerman" while two lumberjacks saw a tree.