The film opens with a documentary-style overview of Uncle Drew, a well-remembered basketball legend who was supposed to play in the Rucker Classic. However, due to an unknown conflict, he and his team disappeared. In the present, Dax Winslow is the underappreciated coach of the Harlem Money and their star player, Casper Jones. Dax spends lavishly to keep both his girlfriend, Jess, and Casper happy, despite being a clerk at Foot Locker. During practice Mookie Bass, an old rival of Dax’s, arrives and taunts him about the upcoming Rucker Classic tournament. In a dream sequence, it is revealed that Dax was an orphan who planned on becoming a basketball player, but was humiliated by Mookie after he had a shot blocked by him in their youth. The next day at work Casper demands expensive new shoes from Dax, who effectively bankrupts himself purchasing them. Despite this, Mookie successfully recruits Casper and the rest of Dax’s team away from him, leading to a confrontation involving Dax forcibly trying to remove Casper’s shoes that is filmed and shown on ESPN. Due to this humiliation, Dax’s girlfriend Jess dumps him and kicks him out of her apartment.
Dejected, Dax has little luck finding players for a new team until the cantankerous Angelo encourages him to seek out Uncle Drew. Drew turns out to be an exceptional basketball player despite his old age. After seeing a demonstration of Drew’s prowess, Dax recruits him for the team, neglecting to inform him about the tournament’s prize money. Drew agrees to join Dax under the condition that they recruit his original teammates.
They set off in Drew’s van and recruit Preacher, who has since become an actual preacher, but incur the wrath of his wife Betty Lou who pursues them as they leave town. They next reunite with the partially blind Lights and the wheelchair bound Boots whose granddaughter, Maya, volunteers at the nursing home looking after them. They escape and make it to the karate dojo of Big Fella. Big Fella is reluctant to join the team, as he still holds a grudge against Drew, but Dax persuades him to join. After his credit card is declined at a gas station, Dax attempts to hustle the coach of a youth girls basketball team to earn money for fuel. Dax’s team loses, but Drew offers up the money to help Dax after learning the real motive for the game, and Maya begins to appreciate him for the way he treats the elders.
Returning to Rucker Park, Drew gives each member of his team gear that restores their faith and abilities, but Big Fella still refuses to cooperate with Drew. During the team’s first game in the tournament Big Fella and Drew tussle on the court, almost costing them the win. Eventually, Drew acknowledges his mistake: sleeping with Big Fella’s now deceased wife before the big game. He admits that he too loved her and the two make amends.
Meanwhile, Dax learns that Mookie and Jess are dating, and begins falling for Maya. After learning about the tournament’s prize money from Angelo and realizing he was misled, Drew angrily confronts Dax. Dax confides in him about his past with Mookie, causing Drew to forgive him. While playing in the semi-finals, Big Fella suddenly has a heart attack and is taken to the hospital. Betty Lou arrives but instead of chastising Preacher, she agrees to fill in as the team’s fifth member.
Dax and his team, now renamed the Harlem Buckets, play against Mookie’s team in the finals who are an even match for them. Late in the game Lights and Casper collide and are both injured, forcing Dax and Mookie to fill in. Dax still lacks self-confidence, but his teammates give him the advice he needs and he manages to make the game-winning shot, beating Mookie and earning everyone’s respect. Returning to the hospital the team reunite with Big Fella, Dax uses the prize money to pay his medical bills, and ESPN now hails Dax as a hero.
During the credits Jess is shown trying to call Dax about getting back together, becoming increasingly distraught when he does not answer.