Though born in Milan, Agrippa lived and worked in Rome, where he was associated with the Confraternity of St. Joseph of the Holy Land and the literary and artistic circle around Cardinal Alessandro Farnese.

In his Treatise on the Science of Arms with Philosophical Dialogue (published in 1553), he proposed dramatic changes in the way swordsmanship was practised at the time.

He also simplified Achille Marozzo's eleven guards down to four: prima, seconda, terza and quarta, which roughly correspond to the hand positions used today in the Italian school.

Based on an inscription in a copy of Agrippa quoted in the last edition of the bibliographic dictionary by Jacques Charles Brunet, Manuel du libraire et de l'amateur des livres (1860–1864), some of the copperplate engravings for the book were attributed to Michelangelo, but modern art historians believe the unknown engraver is more likely to have come from the school of Marcantonio Raimondi.

There is evidence indicating that Agrippa's work may have been the inspiration for the Spanish school of swordplay (commonly referred to as Destreza).