The plot is based on the Indian folk legend about a female spirit who attacks men at night if they are alone and only leaves their clothes behind. The residents of a town named Chanderi believe in the spirit of an angry woman, referred to as "Stree", who stalks men and whisks them away during the four days of a festival every year, causing many disappearances. To protect the residents, "O Stree, come tomorrow" is written in Hindi with bat's blood on the entrances of all homes, men are advised to not roam alone after 10 pm during the festive season, and move in groups for safety - a parallel of instructions women are usually told to follow for their own safety.
Vicky (Rajkummar Rao), a ladies' tailor in Chanderi, falls in love with a mysterious girl (Shraddha Kapoor), who is only seen during that festival season. Her frequent disappearances and the fact that she's not been seen by anybody else makes his friends suspicious, and they start believing that she could be Stree. After one of his friends, Jaana, is kidnapped by Stree, Vicky researches the myth to save him. He comes across a book in a library owned by a paranologist. Vicky, his friend Bittu and the librarian Rudra visit Stree's fort to find Jana. Stree drives away Bittu and Rudra and attacks Vicky but is driven away by the mysterious girl. She tells them that she has been trying to destroy 'Stree' for the last few years after losing someone close to her and that is why she only comes during the festival season. Jaana is found, but he begins behaving abnormally. More men go missing after Jaana, under Stree's control, erases the word "Tomorrow" from the protective phrase outside everyone's homes, leaving it as "O Stree, come"; an invitation.
Vicky and the girl meet the book's author, who informs them that Stree was a beautiful girl that every man in town wanted to marry. Just before her wedding night, her husband was killed and she was violated by the foul men. She has since been searching for her true love. He tells them of a prophecy pointing to a saviour. Vicky appears to have all the characteristics mentioned in the prophecy about the saviour. Vicky, his friends, and the girl make a trap to destroy Stree but Vicky realizes that Stree only desires love and respect. Instead of killing her, the mysterious girl suggests he simply cut her long braid - the source of her powers - so that she will be rendered powerless. He does so, and Stree vanishes. Vicky's mysterious girlfriend leaves the city the next day and Vicky bids her farewell without asking her name. On the bus, the girl places Stree's braid in her own hair. She then vanishes from the bus implying she herself is a witch who has been after Streeâ€™s powers from the braid.
Stree visits again the following year and finds her statue at the town entrance with a new phrase - "O Stree, protect us" - in order to give a message to Stree to protect the people and thus Stree does not enter Chanderi.