Uderzo was born in Normandy, but his parents had recently moved from Italy. His name comes from the Italian village called Oderzo (formerly called Uderzo), where his family tree can be traced. His childhood ambitions were to become an aircraft mechanic, despite his talents in art at an early age. He was actually born colour-blind, and was born with two extra fingers (which were surgically removed). His sight has since greatly improved.

During WWII, the teen-aged Uderzo left Paris and spent a year in Brittany in the west of France, where he was working on a farm and helped with his father's furniture business. Many years later when a location for Asterix's village was to be decided, René Goscinny left the decision entirely up to Uderzo, who had little hesitation in choosing Brittany.

Uderzo was starting a successful career as an artist in Paris after the war in 1945, with creations such as Flamberge and also Clopinard, a small one-legged old man who triumphs against the odds. In 1947-48 he create some other comics, such as Belloy and Arys Buck.

Throughout some more creations and travelling for the next few years, he eventually met Rene Goscinny 1951. The pair became good friends very soon, and decided to work together in 1952 at the newly opened Paris office of the Belgian company, World Press. Their first creation was Jehan Pistolet. In 1958 they began work on Oumpah-pah (until 1962), as well as a few other series. In 1959 Goscinny and Uderzo became editor and artistic director (respectively) of Pilote magazine, a new venture aimed at older children. The magazine's first issue introduced Asterix to the French world, and it was an instant hit.

Asterix was presented as a serial in Pilote, but in 1961 the duo published the first album, Asterix the Gaul, as an individual album. By 1967, the comic had become so popular that both decided to wholly dedicate their time to the series. Ever since Goscinny's tragic death in 1977, Uderzo has been writing and illustrating the books on his own, at a much slower pace (about one album every 3-5 years now, compared to 2 albums per year when working with Goscinny). The main credit on the cover still says "Goscinny and Uderzo".

In 1985, Uderzo was awarded the Knight of the Legion of Honour.