At the begginning of the movie, Megamind always kidnapped her. She has actually been kidnapped so many times that she has become quite casual about the whole ordeal. Even going as far as to try to get in an interview with Minion during one of these kidnappings. She knows just almost everything about Megamind except that he harbors a secret crush on her.
One day, Megamind kidnaps her yet again, Metro Man goes to her rescue yet again, the same predictable routine. It turns out Metro Man's weakness was copper as it drains his power, and when Megamind's death ray hits, it kills the hero and Megamind takes over the city. One night, Roxanne goes to the museum dedicated to Metro Man and bumps into the museum's archivist, Bernard. As she attempts to comfort him about the hero's death, she says the heroes can be made and decides to stand up to Megamind. The next day, she finds the villain's secret hideout and goes inside, along with Bernard in order to try and find out the villain's plans for the city and stop them. After standing up to Megamind and escaping the lair, Roxanne becomes impressed with Bernard for being the only other person to stand up to Megamind except Metro Man. She begins seeing him, and they become close, while all the while Roxanne works on deciphering Megamind's plans. One evening, before going on a date with Bernard, Roxanne finally figures out Megamind's plan: to create a hero so that he'll have someone to fight again. And it turns out that the hero, Titan, was actually Roxanne's cameraman, Hal Stewart. When she goes to her date, a very big secret is revealed completely by mistake: "Bernard" was actually Megamind all along. Roxanne, deeply hurt, dumps him in the rain. However, she looks back before she walks away.
The next morning, Megamind comes to her apartment and tells her that Titan turned evil and he needs her help. Since Titan has Metro Man's powers, they need clues as to what could be his weakness and since Roxanne knows where Metro Man's hideout is, they decide to cooperate. After arriving there, the duo finds out that Metro Man is actually alive and well. The truth was that he got tired being a hero and faked his death in order to retire. However, he won't be helping them because he was done being a hero. After that, Megamind lost his will to fight and goes back to prison. But Roxanne goes and tries to reason with Titan and that backfires as Titan ties her to Metro Tower, the tallest building in the city and uses her to lure out Megamind. Roxanne encourages Megamind to not give up as this was his best quality and that she needs his help right now. Megamind does come to her rescue and saves her, but gets injured in the process. Then Metro Man shows up, saying he never should have left and goes after Titan. The twist is, that it was Minion who was "Megamind", and Roxanne figures out that "Metro Man" was the real Megamind. After Megamind chases Titan off, Roxanne turns off his disguise so that everyone can see who their real hero was. However, Titan comes back and realizes that it was Megamind and not Metro Man because of Megamind's mispronunciation. Roxanne spots Megamind's invisible car, where the one thing that could stop Titan is, and alerts Megamind. He grabs the Defuser gun, but Titan throws him into the air, and it looks like he will fall to his death. Roxanne in the meantime, creeps behind Titan to knock him out with a signpost but abandons that plan and runs when Megamind goes flying and Titan comes after her. She backs into the fountain, with Titan about to kill her, when a dehydrated cube falls in the water and materializes into Megamind, who grabs the gun, and defuses Titan from his powers. Roxanne forgives Megamind and he becomes Metro City's new hero. Roxanne is last seen dancing with Megamind at the musuem inauguration, when their dance ends she leaps into his arms and gives him a kiss on the cheek.