Iwerks was responsible for the distinctive style of the earliest Disney cartoons. The first few Mickey Mouse cartoons were animated almost entirely by Iwerks. He was for many years Walt Disney's best friend, and spent most of his career with Disney. Iwerks and Disney had a falling out, and their friendship was severed when Iwerks accepted a contract with a competitor to leave Disney and start an animation studio under his own name.
The Iwerks Studio opened 1930. Financial backers led by Pat Powers suspected that Iwerks was responsible for much of Disney's early success. However, while animation for a time suffered at Disney from Iwerks departure, it soon rebounded as Disney brought in talented new young animators. The Iwerks Studio enjoyed no great success and failed to rival the top Disney and Fleischer Studios. The backers withdrew further financial support from Iwerks Studio in 1936, and it soon folded. After this, Ub Iwerks worked for a time for Columbia Pictures before returning to work for Disney in 1940.
After his return to Disney Studios, Iwerks mainly worked on developing visual special effects. He is credited as developing the processes for combining live action and animation used in Song of the South.
Iwerks's most famous work outside animating Mickey Mouse was Flip the Frog for his own studio. Flip bears more than a small resemblance to the characters Iwerks drew earlier, Mickey Mouse and Oswald the Lucky Rabbit.
Iwerks was known for his fast work at drawing and animation and his wacky sense of humor. Animator Chuck Jones, who worked for Iwerks' studio in his youth, said "Iwerks is Screwy spelled backwards". Ub Iwerks died of a heart attack in Burbank, California.
A documentary film, The Hand Behind the Mouse: The Ub Iwerks Story was released in 1999.