Charlier was born in Liège, Belgium in 1924. In 1945 he got a job as a draughtsman in Brussels with World Press, the syndicate of Georges Troisfontaines, which worked mainly for the comic strip magazine Spirou. The following year he and artist Victor Hubinon created the four-page comic strip L'Agonie du Bismarck. Charlier wrote the script and also drew the ships and airplanes. In 1947 Charlier and Hubinon began the long-running air-adventure comic strip Buck Danny. After a few years, Charlier stopped all work on the drawings and concentrated only on the scenarios, on the advice of Jijé, then the senior artist at Spirou.

Unable to support himself writing comic scripts at a time when Dupuis concentrated almost solely on the magazine and albums were few and far between, Charlier qualified for a pilots license in 1949 and briefly flew for the airline SABENA.

However the following year Charlier returned to comic strips, collaborating with Hubinon once again to create Tiger Joe for La Libre Junior, the weekly comics supplement to the journal La Libre Belgique. Charlier also continued to supply scripts for Spirou magazine, collaborating with Eddy Paape on the strip Valhardi and, in 1955, with future Asterix artist Albert Uderzo on the comic strip Belloy. Together with Hubinon, he also created some biographical comics like Jean Mermoz and Surcouf. Other long running series he started for Spirou in the early 1950s were La Patrouille des Castors for Mitacq, and in 1951 Les Vraies Histoires de l'Oncle Paul (Uncle Paul's true stories), a weekly comic of four pages telling a true story. The latter series was continued from 1954 on by Octave Joly, and was a place where many young talents published their first comics, including Jean Graton, René Follet and Hermann Huppen.

Charlier, Hubinon, Uderzo, and comic-strip writer René Goscinny founded the comics agency Edifrance and the magazine Pistolin in 1955, and the influential magazine Pilote in 1959. Charlier was editor-in-chief and also wrote two stories for the first issue: Redbeard with Hubinon and Tanguy and Laverdure with Uderzo - these latter two characters would later get their own TV series as well: Les Chevaliers du Ciel, featuring Tanguy and Laverdure, was made by ORTF between 1967 and 1969, an English-dubbed version of the show being released under the title The Aeronauts.

Charlier visited the United States in 1963 and a tour of the American West inspired him to create Fort Navajo, a western series, for Pilote. He chose as artist Jean Giraud (Moebius), then a commercial illustrator who had briefly worked with Jijé on Jerry Spring, a popular European western strip. Fort Navajo, later renamed Blueberry or Lieutenant Blueberry after its main character, became a popular and innovative graphic novel. In 1972 friction among the staff at Pilote caused Charlier to give up his editorial position and he worked in French television until 1976. He then worked as editor-in-chief for two years at Tintin magazine. He continued to write Blueberry and Buck Danny stories.

Jean-Michel Charlier died in Saint-Cloud, France, in 1989. His main series are all continued by other writers, often chosen by Charlier himself.