The entirety of Rear Window takes place in and around the back courtyard connecting apartments in the West Village of New York City. L.B. Jeffries (James Stewart), the resident of one of the second-floor apartments, is a photojournalist who recently broke his leg while on the job. He is going stir crazy, having been stuck inside for the past six weeks. He entertains himself by moving his wheelchair next to the rear window of his apartment and watching his neighbors.
Jeff's chatty nurse, Stella (Thelma Ritter) cautions Jeff about the legal consequences for "Peeping Toms", but Jeff laughs off her warnings. While Stella massages him, Jeff confesses that his girlfriend, Lisa, expects him to marry her but he thinks she's too perfect-Park-Avenue for him. Later, Jeff is awakened by a kiss from Lisa (Grace Kelly). She sets up a fancy take-out dinner for them. After eating, Lisa and Jeff have a serious conversation about their differences. Jeff describes the difficult conditions that Lisa would have to endure as the wife of a traveling photojournalist; he doesn't think that she's meant for "that kind of life." Jeff's stubbornness frustrates Lisa; she loves him and just wants them to be together.
That night, a thunderstorm wakes Jeff up at 2 a.m. He sees the salesman who lives in the building across from his leave his apartment with a briefcase and return an hour later. Strangely, the salesman then leaves with his briefcase once more. Jeff falls asleep. When Jeff wakes up, he sees the salesman return for a second time. Meanwhile, the salesman's wife, who previously appeared to be homebound, is no longer in their apartment. The next day, Jeff watches the salesman wrap a thin saw and a butcher knife in newspaper.
Lisa comes to visit, but she feels like Jeff's mind is elsewhere. He proves her right by sharing his suspicion that the salesman killed his wife and chopped up her body. Lisa is frustrated with Jeff's obsession with watching his neighbors and threatens to leave. Then, she goes quiet when she sees the salesman wrapping heavy ropes around a big, brown chest. Suddenly, Lisa isn't so dismissive; she asks Jeff to tell her everything he's seen. Later, Lisa snoops around and finds out that the salesman's name is Lars Thorwald (Raymond Burr).
Jeff calls his friend, Det. Doyle (Wendell Corey), to report a "neighborhood murder." Meanwhile, Jeff and Stella keep watching Mr. Thorwald's apartment as two uniformed deliverymen carry out the rope-wrapped trunk. Det. Doyle arrives and is immediately skeptical about Jeff's far-flung conclusions. Nevertheless, Doyle agrees to find out where Mrs. Thorwald is. After Doyle leaves, Jeff notices a little dog digging up the flowers that Mr. Thorwald planted in the courtyard the day before. That evening, Doyle returns and tells Jeff that Mrs. Thorwald took a train to Merrittsville the night before and even sent a postcard to her husband informing him of her safe arrival. However, Jeff keeps questioning Doyle's information.
While he is alone that evening, Jeff watches Mr. Thorwald pack all of his clothing. Excited, Jeff calls Doyle's house and leaves an urgent message. Then, he watches Thorwald empty his wife's handbag, the contents of which include her jewelry. Lisa arrives. After getting Jeff's update, Lisa says that Mrs. Thorwald would never leave behind her favorite handbag or her jewelry if she were going on a trip. Lisa speculates that the woman who left the Thorwalds' apartment with Mr. Thorwald was not actually his wife. Doyle comes to Jeff's apartment and systematically dismisses all of Jeff and Lisa's questions. It turns out that the mysterious trunk was filled with Mrs. Thorwald's clothing.
Lisa and Jeff are deflated after Doyle's refusal to take their suspicions seriously and close the window to spend some time alone. But just as Lisa and Jeff start flirting, a loud scream emerges from behind the closed blinds. The woman who sleeps on the fire escape is weeping - someone has strangled her little dog and broken its neck. All the neighbors rush onto their balconies except for Mr. Thorwald, who is sitting in his apartment in the dark. The next day, Lisa and Stella stand beside Jeff while he uses his camera to spy on Mr. Thorwald washing the bathroom walls. Stella comments that there must have been a lot of blood when Mr. Thorwald killed his wife. Jeff then compares two slides he took of the flowerbeds in the courtyard - it is clear that the flowers that Mr. Thorwald planted have gotten shorter over time. He believes that something is buried under them. Jeff writes an anonymous note to Mr. Thorwald that reads, "What have you done with her?"
Stella and Jeff watch as Lisa slips the note under Mr. Thorwald's door. Thorwald comes into the hallway after reading it, but Lisa is already gone. Later, Jeff makes an anonymous phone call to Mr. Thorwald in order to get him out of the apartment, thus making it safe for Lisa and Stella to dig around in the flowerbed. However, nothing is buried there. Since Mr. Thorwald is still out, Lisa decides to shimmy up the fire escape and into his apartment. Unfortunately, Mr. Thorwald returns before Lisa has the chance to escape. Jeff calls the police, but Mr. Thorwald has already found Lisa in his apartment. He attacks her. Luckily, the police show up and take Lisa away. She flashes her ring finger at Jeff, showing him that she has managed to steal Mrs. Thorwald's wedding ring - proof that her disappearance is involuntary. Mr. Thorwald sees Lisa signaling to Jeff before the police take her away. Stella runs to the police station with money to bail Lisa out.
Jeff is alone in his apartment, sitting in the dark, when Thorwald comes inside. He demands that Jeff return the wedding ring, but Jeff explains that Lisa has given it to the police. Thorwald attacks Jeff just as Doyle and Lisa arrive at Thorwald's apartment across the courtyard. Jeff calls out their names and they run down the stairs, but Thorwald is already strangling Jeff; he dangles him from the window. The policemen grab Thorwald from inside Jeff's apartment, but Jeff falls. Thorwald makes a full confession to the police - he disposed of Mrs. Thorwald's body in the East River. Then, he killed the dog for digging where her head was buried. After that, he moved the head to a hatbox inside.
In the epilogue, Jeff's neighbors' lives resume. Meanwhile, he's asleep in his wheelchair, now with both legs in casts. Lisa is sitting on the bed reading a book called "Beyond the High Himalayas." Once she sees that Jeff is asleep, she puts down the book and picks up Harper's Bazaar.