In the early portion of the movie, when Megamind has Metro Man trapped in the real abandoned observatory, look closely at the scene where the images of Megamind and Metro Man are being projected upon the buildings. Just after Megamind orders Minion to fire the death beam, there is a single frame where Metro Man fades slightly from the observatory screen and reappears faintly behind Megamind on the opposite screen. This foreshadowed Metro Man faking his death through superspeed.
To promote the film, Will Ferrell assembled 1,580 of his friends and their acquaintances at a superhero costume function. This party set a Guinness World Record for the largest gathering of superheroes.
There are numerous references to Superman in this film: The way Megamind's parents put him in a capsule to Earth just before his planet is destroyed. The love interest is a reporter. Hal's "space dad" is modelled after Marlon Brando, as Superman (1978)'s father in Richard Donner's film version. Almost all of Metro Man's super powers are the same as Superman's. Megamind's pronunciation of Metro City has the same stress pattern as 'Metropolis" in Superman. Megamind takes on a bespectacled secret identity similar to Clark Kent. In the Metro Man Museum, there's a statue of Metro Man preparing to catch an airplane. This is a reference to John Byrne's Superman comics, where Superman made his first appearance by catching a plane and saving Lois Lane.
The film was originally titled "Master Mind". However, the name had already been trademarked by the makers of the 1970s board game and television show Mastermind (1972), so it could not be used. It was then going to be titled "Oobermind", which was a misspelling of the term "über-mind." The word "über" refers to something that is large or great; in this case, the title character's over-swollen skull/brain. But it didn't sound right, so it was revised to become "Megamind".
When Megamind (Will Ferrell) is channel surfing towards the end of the movie, he comes upon a news report of a squirrel water skiing. Ferrell had played Ron Burgundy in Anchorman: The Legend of Ron Burgundy (2004), in which Burgundy does a report on a water skiing squirrel.
Megamind plays a snippet of Minnie Ripperton's "Loving You" after supposedly killing Metro Man and taking over Metro City. Will Ferrell, the voice of Megamind, was castmates on Saturday Night Live (1975) with Ripperton's daughter, Maya Rudolph.
The idea that Megamind chose the name "Titan" for Hal's alter ego, because it was the only name he could trademark is amusing, but not factual. There have been several superheroes named "Titan". Most notably, by Dark Horse comics beginning in 1993.
The dresses Roxanne wears throughout the film visualize her relationship with Megamind. When she first appears, she wears a red dress, when Megamind was her enemy (blue is the opposite of red). Later, she wears purple, as she and Megamind develop a better relationship. Roxanne's final dress is blue, as she has fully accepted Megamind.
When Metro Man faked his own death by escaping in the last millisecond, and replacing his body with a skeleton, it directly mimics events in the major DC Comics storyline "52", which documents a full year where Superman, Batman, and Wonder Woman have disappeared from the public eye and are presumed dead (similar to the events of "Megamind"). In "52", time-travelling superhero Booster Gold also faked his own death in an identical fashion to Metro Man by replacing his body with a skeleton at the last second.
During the opening of the Metro Man museum, "A Little Less Conversation" by Elvis Presley plays. This foreshadows the later part of the film, when it is revealed that Metro Man faked his own death, grew a beard, and lives in hiding, as persistent rumors claim Elvis did.
Hal the cameraman is seen wearing a yellow "sad face" badge. This is a tribute to the Alan Moore comic "Watchmen", where The Comedian wore a yellow "smiley face" badge. Since The Comedian was an unbalanced vigilante, this foreshadows Hal's instability and corruption.
At the end, when Michael Jackson's track "Bad" was playing, and Hal was dancing along it, the Warden was seen to play along with two of his guards. Their "head shaking step" was taken from Saturday Night Live (1975)'s "what is love" skit, which also starred Will Ferrell.
Megamind lands in a prison, where he is raised to be a criminal. This alludes to "Superman: Red Son", a graphic novel which demonstrates what could have happened if the infant Superman had crash-landed, and was raised in the Soviet Union. Both also have similar endings: the hero retires by pretending to be dead, goes into hiding, and leaves his work in the hands of his former nemesis.
Minion's suits increase in scale throughout the film: he is first seen wearing a remote-controlled suit in Megamind's childhood. He is seen throughout the film in his own robotic suit. At the end of the film, he is riding the giant battle suit.
In the office, where Megamind in lamenting his destruction of Metro Man, the camera pans across the room until it stops on Megamind addressing an infamous "Drinking Bird". As the camera pans, you can see what appears to be the Ark of the Covenant from Raiders of the Lost Ark (1981) as well as what seems to be the title statue from The Maltese Falcon (1941) on the desk to the right of Megamind, as he begins to address the Drinking Bird.
At school, the young Megamind dehydrates Minion. When re-hydrated, Minion is floating upside down, pretending he is dead, foreshadowing faking his demise later in the movie. In the same scene, Metro Man is playing "Itsy Bitsy Spider" on the guitar in the background, also foreshadowing becoming "Music Man".
After Megamind and Roxanne Richie discover Metro Man in hiding, he sings a snippet of a song for them. The lyrics being, "I have eyes that can see right through lead". The tune which he sings it to is Nirvana''s 1991 song "Come As You Are". Appropriately, lead is the one thing that Superman cannot see through.
During the climax, Minion (David Cross) is able to let Megamind (Will Ferrell) out of prison to face off Titan (Jonah Hill) and become a hero, in disguise as the prison warden (J.K. Simmons) after apologizing for his villainry. Cross and Simmons appeared in DreamWorks Animation's Kung Fu Panda 3 (2016).