De Manchicourt was born at Béthune. Little is known of his early life other than that he was a choirboy at Arras in 1525; later in life he had a succession of posts in Arras, Tours and Tournai, before going to Spain to be master of the Flemish chapel (capilla flamenca) at the court of Philip II, where he stayed for the remainder of his life.
Similar to many composers of the early to mid 16th century, he predominantly wrote masses, motets and chansons. His motets are particularly significant as they show the three separate stages of early sixteenth century motet development, highly unusual to find in the work of a single composer. In his earliest motets one can hear the influence of Ockeghem; in his middle period works, the paired imitation style of Josquin des Prez; and in his late works the stylistic refinement, well-crafted melodic lines and pervasive imitation recall Gombert.
Manchicourt is an excellent example of a Franco-Flemish composer who learned his craft and art in northern Europe, and then assisted in the diffusion of the style by traveling to another region and composing and performing there. The movement of these many skilled composers out of Flanders and northern France created what was one of the first truly international styles since the original diffusion of Gregorian chant during the reign of Charlemagne.
He died in Madrid and was succeeded as maestro de capilla by Jean de Bonmarché.