In the final game coming out of a timeout with mere seconds left on the clock, Uncle Drew (Kyrie Irving) reminds Preacher (Chris Webber) that they have no more timeouts. This is in reference to an incident during the NCAA Men's Division I Basketball Tournament on April 5, 1993. During that game, the real life Webber called a timeout with 11 seconds remaining in the game. Unfortunately, his team, the Michigan Wolverines, who were down 73-71 against North Carolina, didn't have any timeouts left. The call earned Webber a technical foul, and ended up costing the Wolverines the chance to win. Although Webber went on to have an illustrious career in the NBA, he continues to receive ridicule for that error.

Kyrie Irving began portraying the character Uncle Drew in 2012 in commercials for Pepsi Max. PepsiCo partnered with Temple Hill Entertainment to produce this film.

The character played by Lil Rel Howery expresses fear of being in the woods and kidnapped because he's seen the movie Get Out. Howery actually appeared in Get Out as a TSA agent.

Kyrie Irving was actually nicknamed "Uncle Drew" because of the character from the Pepsi Max commercials and also because of his offensive prowess in the NBA. He perfomed crossover moves which, at times, would cause other players to stumble, just like his 70 year old character against younger people in the park. In addition, his middle name is Andrew.

Erica Ash and Tiffany Haddish both acted in the series Real Husbands of Hollywood (2013).

In the outtakes during the credits, Kentucky Wildcats coach John Calipari asks Uncle Drew if he wants to play for his team. Uncle Drew tells him "No, I'm more of a Blue Devils guy." Kyrie Irving briefly played for the Duke Blue Devils before turning pro.

Despite the fact that the character of Uncle Drew is supposed to be in his 70's, Kyrie Irving was only 25 during filming, and had portrayed the character since he was 19. The other characters that make up Uncle Drew's basketball team roster are supposed to be around the same age, but during Uncle Drew (2018)'s production, Nate Robinson (Boots) was 33, Chris Webber (Preacher) and Lisa Leslie (Betty Lou) were both 44, Shaquille O'Neal (Big Fella) was 45, and Reggie Miller (Lights) was 51.

After Big Fella (Shaquille O'Neal) knocks him out with a sucker punch, Uncle Drew says, "That's the first free throw you ever made". Shaq was notoriously bad at free throws, making only slightly more than half of them in his career.

Tiffany Haddish and Lil Rel Howery worked together on The Carmichael Show (2015).

Both Kyrie Irving (Uncle Drew) and Shaquille O'Neal (Big Fella) played on the Cleveland Cavaliers with LeBron James, although they missed playing together on the same team by one year. O'Neal had been traded to the Boston Celtics in 2010, the year the Cavaliers drafted Irving. Irving would go on to play for the Celtics in 2017.