As a tribute to video games, Pixels has a lot of Shout Outs to them, but not only.
- Pac-Man attacks New York City during the second battle and the cars that chase him are named after ghosts in the game.
- Donkey Kong is the antagonist in the finale, and it's also the game that the finalists of the World Championship play in 1982. Jumpman appears later as an attacker.
- Centipede is the enemy of the London battle.
- Galaga attacks the Guam base.
- Space Invaders are briefly seen, and at one point Sam asks Ludlow whether he played the game recently, because he's "invading [his] personal space".
- Arkanoid is used to destroy Taj Mahal.
- Q*bert is given to humans as a trophy for winning against Pac-Man and joins the heroes.
- The dog from Duck Hunt is another trophy.
- Lady Lisa looks like a shout out to Kill Bill and/or Tomb Raider.
- Bill gets a Chewbacca mask in the crane game and is called Chewie as a kid.
- Sam calls photon guns "blasters".
- Lowell claims that "JFK shot first", a reference to Star Wars meme of "Han shot first".
- Mattie is seen playing The Last of Us.
- When asked about classic games, Mattie lists Halo and Call of Duty.
- One of the games Sam teaches the SEALs to play are Asteroids.
- Tetris blocks are destroying Washington during the final battle.
- A Smurf is seen dancing on the street and is promptly blown by Violet for being creepy.
- During the final battle, Queen's "We Will Rock You" plays, remixed slightly.
- Alien leader appears to Sam, Violet, Q*bert and Bill as Max Headroom.
- Alien messages to humans consist of mashed-up videos of Madonna, Hall and Oates, and Ronald Reagan among others.
- At one point, Ludlow tells Michael that he has "a beautiful mind".
- Ludlow tells Sam that he's been browsing 4chan in search of alien life. He found nothing.
A dozen other video game characters make cameo appearances.
