Nine years ago, Woody and Bo Peep rescued Andy's remote control car, RC, from being washed away in a storm, before Bo and her lamp were donated to a new owner. Woody was distraught but Bo had accepted her fate as part of a toy's life.

In the present day, after a college-bound Andy has donated his toys to Bonnie, Woody struggles to adapt as Bonnie shows little interest in playing with him and her toys already have a leader. When she creates a doll from a spork at her kindergarten orientation, it comes to life as Forky. Forky suffers an existential crisis, seeing himself as trash, not a toy. As Forky quickly becomes Bonnie's favorite toy, Woody tries to stop Forky from throwing himself away.

When Bonnie's family goes on a road trip, Forky jumps out of the window of the RV, and Woody goes after him. As they walk to the park, Woody convinces Forky that his place is with Bonnie, and Forky overcomes his existential crisis. As they pass an antique store, he recognizes Bo Peep's lamp in the window, and detours inside to find her. They encounter a talking doll named Gabby Gabby and her ventriloquist dummy friends, who try to take Woody's voicebox to replace Gabby's broken one. Woody escapes, though Forky becomes Gabby's prisoner. At a playground nearby, Woody reunites with Bo and her sheep, who have become "lost toys", free from owners and able to do as they please, along with their new friend Giggle McDimples. They agree to help Woody rescue Forky.

Buzz Lightyear, trying to find Woody, gets lost in a traveling carnival and encounters prize toys Bunny and Ducky. They find Woody and Bo, who takes them to stunt bike toy Duke Caboom. They attempt to rescue Forky, only to nearly get killed by the store owner's cat. The toys refuse to go back due to the danger, but Woody, desperate to be necessary to Bonnie, inadvertently insults Bo and leaves her and Buzz behind. He is left alone to rescue Forky, but when he confronts Gabby, she explains that she means no harm and has wanted a child's love for more than 60 years. Woody agrees to give his voicebox to Gabby, but the child whom she wanted as an owner rejects her.

Woody sends Forky to the RV and convinces Gabby to return to Bonnie's house with him. Bo, Caboom, and the rest of the gang return and help the pair escape and Bo and Woody reconcile. Jessie rallies Bonnie's toys to use the RV to drive back to the fair. On the way, Gabby notices a lost child at the carnival and leaves the group to comfort her until the parents arrive; the girl takes Gabby with her.

Woody is hesitant to leave Bo again; Buzz assures him that Bonnie will be okay without him. Woody shares an emotional goodbye with his friends, and joins Bo as a "lost toy". Some time later, Bonnie creates a companion for Forky from a plastic knife, while the "lost toys" travel with the carnival and help prize toys find owners.

• Tom Hanks as Woody
• Tim Allen as Buzz Lightyear
• Annie Potts as Bo Peep
• Tony Hale as Forky
• Keegan-Michael Key as Ducky
• Jordan Peele as Bunny
• Madeleine McGraw as Bonnie
• Christina Hendricks as Gabby Gabby
• Keanu Reeves as Duke Caboom
• Ally Maki as Giggle McDimples
• Jay Hernandez as Bonnie's dad
• Lori Alan as Bonnie's mom
• Joan Cusack as Jessie
• Wallace Shawn as Rex
• John Ratzenberger as Hamm
• Blake Clark as Slinky Dog
• Don Rickles as Mr. Potato Head
• Estelle Harris as Mrs. Potato Head
• Jeff Pidgeon as Aliens
• Bonnie Hunt as Dolly
• Kristen Schaal as Trixie
• Timothy Dalton as Mr. Pricklepants
• Jeff Garlin as Buttercup
• Emily Davis as Billy, Goat, and Gruff
• John Morris as Andy
• Laurie Metcalf as Andy's mother
• June Squibb as Margaret
• Carl Weathers as Combat Carl
• Maliah Bargas-Good as Lost Girl
• Juliana Hansen as Miss Wendy
• Steve Purcell as Benson and The Dummies
• Lila Sage Bromley as Harmony
• Mel Brooks as Melephant Brooks
• Carol Burnett as Chairol Burnett
• Betty White as Bitey White
• Carl Reiner as Carl Reineroceros
• Alan Oppenheimer as Old Timer

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Randy Newman, who composed and wrote songs for the previous three films, was confirmed to be returning during the 2015 D23 Expo. Director Josh Cooley said that he hired Newman to return because he "can't imagine making a fourth [film] without Randy Newman." Newman wrote new themes for Bonnie, Gabby Gabby, and Duke Caboom, with the latter's featuring accordions and mandolins to represent the character's memories of rejection. He also wrote a "subordinate theme" for Forky. Newman also reused his previous orchestral themes from the first three films. He wrote two new songs for the film, titled "The Ballad of the Lonesome Cowboy" and "I Can't Let You Throw Yourself Away", with Newman also performing the latter. On June 5, 2019, Chris Stapleton's version of "Cowboy" was released as a single. The film's soundtrack, featuring Newman's score, Stapleton's and Newman's versions of the two new songs, and Newman's "You've Got a Friend in Me", was released on June 21, 2019.