Megamind accidentally shoots the hero DNA capsule up Hal's nose. With Minion they follow Hal to his apartment and (disguised as a Marlon Brando step-space dad and a badly disguised space step-mum) they instruct him in the ways of being a good superhero.
Meanwhile, disguised as Bernard, Megamind is becoming sweet on Roxanne. He wants to be the good guy, and sends poor Minion away.
Now that Hal has controlled his powers, he tries it on with Roxanne with some fake-rescues, but it all goes badly wrong and she turns down his advances. Roxanne meets Bernard for a date, but as they kiss she catches his watch and he turns back into Megamind. She's repulsed.
Spurned, Megamind declares war on his creation, Titan. He dons the "Black Mamba" cape, gets into a giant black robot, and storms down the city streets all to AC/DC. Titan doesn't show.
Megamind calls round Hal's apartment, to see that he has become a thief, using his powers for evil. Angry, Megamind shows him the various disguises - ending with Bernard. A jealous Titan takes the fight to Megamind.
Without the usual wity remarks, Megamind is not ready for Titan's onslaught and needs to use the fail-safe - a giant ball of copper. Titan breaks out, but Megamind manages to get away.
Titan is congratulated by the city mayor - but flicks him away and tells them that he has come to take over. He starts to burn the city with his laser vision.
Megamind calls round Roxanne's apartment and together they travel to Metroman's old lair - beneath the School. The lair is still clean and tidy - and inside they find a dishevelled Metroman still alive. He tells them that he got sick of his old daily life and decided to follow his heart - to become Musicman! He is unwilling to help them.
Megamind walks into his old cell to be locked up again for his 87 life sentences. On TV we see that Titan has captured Roxanne and has given Megamind 1hour to rescue her. Megamind apologises to the warden, and regrets mistreating Minion. The warden turns into Minion, and he unlocks the door. Friends again, they go off to save the day - knowing they'll lose again!
With his brain robot buddies, Megamind flies in above the Metro City tower and rescues Roxanne. They get away on a rocket bike as Titan follows with the Metro City spire. They can't outrun Titan, and it looks like Megamind has been speared.
Titan throws a bus at Roxanne when suddenly Metroman shows up. He threatens Titan who wisely flies away.
Roxanne finds that the defeated Megamind is in fact Minion - and she turns the watch on Metroman to find Megamind. Suddenly Titan shows back up, because Megamind mispronounced "Metro City" before. They fight and Megamind is almost vapourised, until he finally finds his invisible car and manages to retrieve the DNA gun and shoot it into Titan's mouth - turning him back into Hal.
Later, Megamind enters the stage to rapturous applause at an event to unveil his statue, much like the earlier scene for Metroman. "Musicman" is in the crowd to wish his old buddy luck. Megamind gets the girl, and together they dance out to Michael Jackson's 'Bad'.
After credits - Minion is washing Megamind's outfit when Bernard starts to whizz around in the tumble-dryer, having been hydrated. He moans about having a bad day, until Minion uses the 'forget me not' stick on him.