Leaves of globe artichoke are food industry byproducts gaining interest due to their therapeutic and nutraceutical potential. The total phenolics, flavonoids, and flavonols content as well as radical scavenging capacity and reducing antioxidant power were determined in leaves of 19 artichoke cultivars. An untargeted analysis based on high-resolution mass spectrometry was then carried out to profile phenolic compounds and sesquiterpene lactones (STLs). The phenolic profile of leaf extracts from different cultivars was widely diverse and included flavonoids, hydroxycinnamic acids, tyrosols, and lignans. Grosheimin and its derivative were the most abundant STLs in all artichoke cultivars. Among the examined cultivars, “Campagnano”, “Grato 1”, and “Violetto di Provenza” were found to be the richest in polyphenols and presented the highest antioxidant activity, whereas “Blanca de Tudela” and “Carderas” were characterized by a high STLs content. Hence, specific artichoke cultivars can be selected as the source of natural antioxidants with a desired profile of nutraceutical compounds like phenolics and STLs.