Nickelodeon producer Mary Harrington discovered Jhonen Vasquez through his comic Johnny the Homicidal Maniac and asked him to pitch an animated series, even though he had no animation experience at the time.

Vasquez came up with the entire premise for Invader Zim in about an hour while lying in bed unable to sleep, after briefly considering a lighter Mork & Mindy-style concept that he ultimately rejected.

Mark Hamill was originally cast as the voice of Zim for the pilot but was replaced before it was shown to Nickelodeon executives because Vasquez felt his voice wasn't right for the character; Billy West voiced the pilot before Richard Steven Horvitz took over for the series.

Vasquez cast his friend Rosearik Rikki Simons as GIR specifically because he sounded unprofessional and 'bad at it', which fit the character's broken, malfunctioning personality; Simons' voice was later edited to sound higher-pitched and metallic.

An illustrator secretly inserted a single-frame drawing of 'Bloody GIR' (created by Jhonen Vasquez) into the episode 'Bad, Bad Rubber Piggy' and scattered it through the last fourteen episodes without Nickelodeon's knowledge until after the show's cancellation.

Invader Zim used 250–350 storyboard pages per episode to capture precise character movement, far more than the typical 80–120 pages for standard eleven-minute animated series.

The episode 'Zim Eats Waffles' was originally intended to be one continuous shot in an attempt at the longest single shot in animation history, though the idea was scaled back due to storytelling limitations; most of the episode still remained one continuous scene.

Nickelodeon censored several episodes for content deemed too violent or sensitive, including changing a scene in 'Door to Door' that resembled a destroyed New York City due to similarities with 9/11, and pulling 'Hamstergeddon' from rotation after the attacks because it depicted falling buildings.

Nickelodeon canceled Invader Zim after only 27 completed episodes instead of the originally ordered 40, citing poor ratings among its core 6-10 year old demographic and the high production costs of the show.