It begins after Red and her companion narrowly escaped an attack by the Camerata. Red retrieves the Transistor, who narrates the game, from the body of a nearby man. Together, they traverse the Goldwalk district, the canals, the Promenade, and the Empty Set. Along the way, they discover the bodies of several key individuals of Cloudbank, including Lillian Platt, Wave Tennegan, and others. From these bodies, the Transistor is able to absorb their Trace data, unlocking more Functions for Red to use in combat.
After returning to the stage where Red once performed, it's revealed through a cutscene that after her performance, she was ambushed by the Camerata. They attempted to kill her with the Transistor (presumably to download her into the device), but her companion jumped in front of her and took the blow. According to Sybil's file, she likely told the rest of the Camerata that they would be able to find Red alone, but was hoping they would get rid of Red's companion in their ambush attempt. Somehow, when Red's companion was downloaded into the Transistor, his personality took over and he was able to speak and communicate to Red through the device. It's revealed that Red's outfit in-game is the result of her having to tear her stage gown for mobility, and that the jacket she wears is actually that of her companion's. A fight with Sybil ensues, with the former Camerata member being 98% processed. Sybil makes powerful attacks with her parasol and has three "chances" (lives), returning each time with greater health before she is completely defeated. Once absorbed into the Transistor, she tells him and Red where to find two of the remaining members of the Camerata.
Red and the Transistor continue through Highrise, past admin centers, and eventually to Bracket Towers, where two other members are located. On the way, they encounter the Spine of the World, which was apparently a landmark of Cloudbank, but now takes the form of a huge Processed creature. It affects the Transistor a great deal, although Red's combat abilities are unhindered. The Transistor's speech becomes slurred and dazed -- almost like a drunken state. The circle near its hilt glows a brighter red, and sparks continually. The Transistor remains in this state -- and Red suffers surprise attacks from the Spine's tail -- until it is defeated when Red destroys its heart.
After defeating the Spine, Red and the Transistor are able to continue on to the Bracket Towers. Asher Kendrell communicates with Red via corrupted OVC terminals. claiming that he and Grant have "walled themselves in" to keep the Process out. Asher seems remorseful for what has happened to Cloudbank, with Grant apparently in worse condition, but the Transistor doesn't believe Asher's guilt is real until the latter attempts to get a message out to Cloudbank (via OVC), naming all the members of the Camerata, and claiming responsibility for the Process infestation of the city. Red must activate security consoles in both the Archives and the Maintenance Wing in order to unlock the door to access the Kendrells' sanctuary on the roof. Upon entering, she discovers that they have both committed suicide. Grant was unable to cope with losing the Transistor and the destruction of Cloudbank, and Asher was unwilling to continue without him. Gathering their Trace data points Red and the Transistor on to the last remaining member of the Camerata: Royce Bracket.
Red and the Transistor must essentially backtrack to the Fairview district where Royce is waiting. They ride a Process swarm back to Red's stage, the Empty Set, which has been Processed significantly since they were last there. The two continue back through Goldwalk and the canals, which have also been heavily Processed. Red is able to construct a bridge to Fairview using just the Transistor. Fairview has been Processed completely. Royce communicates to Red and the Transistor by robot proxy, offering a truce so that they can be rid of the Process. Red must take the Transistor to the Cradle, where it can affect and change the city to the fullest. Royce warns that they do not have much time before the Process finds them. The Transistor is activated, and both Red and Royce are pulled into it. Once inside the Transistor, Royce is also armed with a Transistor of his own. He tells Red that only one of them can leave in order to change Cloudbank back to how it was -- using the Transistor as brush to a canvas -- apologizes, then begins to fight her using the same turn-based system Red has been using to fight the Process.
After defeating Royce, Red returns to Cloudbank. She returns to the starting point of the game, to the body of the man she found the Transistor in, un-Processing him from the white blocks around him. The Transistor asks excitedly what districts Red plans to repair first, but she has other ideas. She gives the Transistor a final embrace before setting it down on the ground in front of the man. She sits down, wraps the man's arm around her shoulders, and despite its pleadings, kills herself with the Transistor.
The credits depict the man and Red inside the Transistor, in a field in front of a barn -- presumably a representation of The Country. They greet each other, indicating that Red has her voice back. The credit song also features male vocals for the first time in the game, harmonizing with those that represent Red.
Red | The Process | The Transistor | Cloudbank | Sandbox | Backdoors | Locations | OVC Terminal | Junction Jan's | Access Points | Fairview | Camerata | The Story | The Country | The Spine of the World