The film opens with Thelma Post (June Squibb) trying to use the internet while her grandson Danny (Fred Hechinger) tries to teach her. Thelma is 93 years old and widowed for two years following the loss of her husband Teddy. She enjoys spending time with Danny, though she feels he often dotes on her too much and isn’t taking enough responsibility for his own life.
Thelma later gets a phone call from an unknown number. The caller claims to be Danny, saying that he’s in jail after getting into a car accident. He says that someone else will call her, and seconds later, another unknown number calls Thelma. The person on the other end tells her to deliver $10,000 to an address to get Danny out of jail.
Thelma tries to get in touch with Danny, but he won’t answer his phone. She then tries her daughter/Danny’s mom Gail (Parker Posey) and her husband/Danny’s dad Alan (Clark Gregg), but to no avail. Thelma gathers the money and drops the envelope off at the post office. After Gail answers and hears Thelma’s story, she frantically calls Danny, who eventually picks up. The family meets with Thelma and goes to the post office to see if anything can be done about the package, but they get no help since Thelma cannot remember the address where she sent it.
The family tries to be with Thelma now that she knows she’s been scammed, but Thelma isn’t ready to give up. She tries to phone her friends for help, but most of them are dead or moved away. After recovering the address where she sent the package, Thelma then has Danny bring her to a retirement home where her friend Ben (Richard Roundtree) lives. Ben has been trying to keep in touch with Thelma and make plans to see her, but she has been avoiding him since Teddy died.
At the retirement home, Ben is prepping for a performance of “Annie” before Thelma arrives. She tells Ben about what has happened to her, and he tries to offer assistance. Thelma sees Ben’s new red scooter and asks to give it a try. She instead makes an attempt to flee the retirement home with the scooter, prompting Ben to chase after her on someone else’s scooter. Ben manages to catch Thelma and tells her he will not let her go alone. They flee the premises before Danny goes inside to find Thelma (she promised him she would only take 30 minutes inside). When he realizes Thelma is missing, he contacts his parents.
Thelma and Ben stop at the home of their senile friend Mona (Bunny Levine) so that Thelma can get a gun from her while Ben distracts her. The two enter Mona’s home and find her alone and forgetful. Ben chats with Mona while Thelma tries to carefully make her way up the stairs without slipping. She finds Mona’s gun but gets startled by a cockroach and drops it, causing it to fire a round. Thelma goes back to Ben and bids Mona farewell, though they later discuss the sad state of Mona’s life now.
Danny and his parents talk to two retirement home employees, Rochelle (Nicole Byer) and Colin (Quinn Beswick), while they try to figure out where Thelma and Ben could have gone. It is revealed that Thelma had a recent amnesiac episode, and they fear that she doesn’t even know where she is at the moment. Danny then finds that Thelma accidentally posted a picture of her location on Instagram, allowing the family to see that she is at a gas station.
Thelma and Ben get ready to keep moving until Thelma sees the family arriving to get her. She and Ben try to hide but hit a dead end. Thelma throws away her LifeLine bracelet to throw off her location. When Danny gets the notification, they try to follow it, allowing Thelma and Ben an opportunity to get away. Danny then vents to Gail and Alan since he feels he is a screw-up who can’t do anything right with his life, also citing his recent breakup with his girlfriend Allie (Coral Peña). His parents try to reassure him he is not a failure. Danny later tries to call Allie and speaks with her about his feelings.
Thelma and Ben end up in a sketchy neighborhood. They get into an argument over how Thelma has been pushing away the last few people left in her life. A driver then destroys Ben’s scooter since it was left on the street. Ben ends up leaving to go back to the retirement home while Thelma decides to keep on going. While walking through a field, Thelma trips and falls. Unable to pick herself up, she sadly resigns to her situation until Ben returns to help. They get a ride, and Ben gives them the address that Thelma was heading to, intent on seeing her mission through to the end.
The two arrive at the address, which is a UPS store. They find the PO box and wait for someone to come open it. A young man, Michael (Aidan Fiske), opens it and starts walking toward an antique store. Thelma and Ben follow, with Ben waiting outside while Thelma tries to record a confession. Thelma enters and confronts Michael and his grandfather, Harvey (Malcolm McDowell), the other caller. She demands her money back, but Harvey says it has already been deposited into his account. He tries to weasel his way into a deal with Thelma, but she refuses. Michael attempts to run for it, but Ben causes him to trip and knock himself out.
Thelma draws her gun and gets Harvey to back off while Ben holds the gun at him, and she attempts to transfer the money back to her account. She calls Danny, who starts rushing towards her location while trying to guide her over the phone. Michael regains consciousness and goes back in, but Thelma gets him to turn on Harvey since she heard him refer to Michael as a dumbass. Harvey defends his actions because his store is failing and he just “wants to keep the lights on”, as well as the fact that he is an old man who requires an oxygen tank. Thelma leaves Harvey with $500 after transferring the rest back to her account, and then shoots his computer to ensure he can’t try to undo it. Thelma then takes Harvey’s cigarette and throws it in the garbage, unknowingly igniting a gas tank inside and doing a badass walk as it explodes. Danny then arrives to pick up Thelma and Ben, and they return to a warm embrace by Gail and Alan. The family then watches Ben’s show.
Danny later brings Thelma to Teddy’s grave to bring flowers. She then tells Danny that she knows he will be fine when she is gone.
During the credits, a clip is shown of the real Thelma (grandmother of the film’s director Josh Margolin) looking at trees and saying “What spirit!”, as her film self did earlier. It ends with the words, “For Thelma”.
The film is dedicated to Richard Roundtree.