Approximately one-third of the waste biomass from the cultivation of guayule (Parthenium argentatumA. Gray) for natural rubber production is leaf tissue; however, whether it can be valorized is not known. Guayulins and argentatins are potential high-value products that can be recovered from guayule resin during rubber/latex processing. Argentatins are highly abundant in guayule stem resin; however, unlike the guayulins, their occurrence in leaves has not been investigated. The present study determined the content of argentatins and isoargentatins A and B in the leaves of a pure guayule accession (R1040) and two hybrids (CAL-1 and AZ-2) under conditions of irrigation and non-irrigation. The resin content in leaves was ~10%, which provides a suitable starting point for economic exploitation. The highest production of argentatins occurred in plants under irrigation, with yields of 4.2 and 3.6 kg ha−1for R1040 and AZ-2, respectively. The R1040 accession had the highest percentage of resin and the greatest total argentatin content (24.5 g kg−1dried leaf), principally due to the abundance of argentatin A. Contrastingly, CAL-1 consistently showed the lowest argentatin content based on dried leaf weight and production (0.6 kg ha−1). The substantial abundance of argentatins in guayule leaves suggests the potential for future exploitation.