Historia medicinal (1565–1574) is an educational work that sought to promote knowledge of American phytotherapy for academic and economic purposes. This educational aim was accomplished after its publishing success in Spain and other European countries. Our objective is to examine the American words Nicolas Monardes chose and assess the degree of penetration of Native American loanwords and Americanised hispanicisms which have become fully incorporated into current American Spanish. The degree of penetration is measured through the variables with which they appear in the text (loanwords, number of appearances with or without explanation, used in medicine, medical term). 93 words were analysed using quantitative methodology and different degrees of penetration were detected. These terms included Native American loanwords, mediaeval medical hispanicisms, Spanish words created to describe American reality and neologisms that were widespread in the 16th century.