Perezone, a sesquiterpene quinone, is a very important molecule due to its pharmacological activities in addition to the fact that it is considered to be the first secondary metabolite isolated in the new world (America–Mexico, 1852). This study aims to offer a green comparative study about the extraction of the target molecule from the roots of the vegetable specimen Acourtia platyphilla (A. Grey). The study was performed comparing five different modes of extraction: supercritical CO2, electromagnetic infrared and microwave irradiations, mechanical-wave ultrasound versus typical mantle heating procedure. An exhaustive comparative-discussion of the obtained results is provided. It is worth noting that the corresponding quantifications were established using 1H NMR, correlating appropriately the integrals of the vinylic proton H-6 of perezone with the aromatic singlet of p-dinitrobenzene employed as an internal reference. It is also important to highlight that the four presented procedures are novel modes to extract perezone. Finally, a complementary study about the solubility of the target sesquiterpene quinone related to the use of supercritical CO2 is also reported.