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<i>Hylocereus</i> spp. present two varieties of commercial interest due to their color, organoleptic characteristics, and nutritional contribution, such as <i>Hylocerous polyrhizus</i> and <i>Selenicerus undatus</i>. The fruit recognized as dragon fruit or Pitahaya is an exotic fruit whose pulp is consumed, while the peel is discarded during the process. Studies indicate that the pulp has vitamin C and betalains, and seeds are rich in essential fatty acids, compounds that can contribute to the prevention of chronic non-communicable diseases (cancer, hypertension, and diabetes). In the present study, polyphenolic compounds, biological activity, and fatty acids present in the peel of the two varieties of pitahaya peel were evaluated, showing as a result that the variety <i>S. undatus</i> had higher antioxidant activity with 51% related to the presence of flavonoids 357 mgRE/g sample and fatty acids (hexadecanoic acid and linoleate) with 0.310 and 0.248 mg AG/g sample, respectively. On the other hand, <i>H. polyrhizuun</i> showed a significant difference in the inhibitory activity of amylase and glucosidase enzymes with 68% and 67%, respectively. We conclude that pitahaya peel has potential health effects and demonstrate that methylated fatty acids could be precursors to betalain formation, as well as showing effects against senescence and as a biological control against insects; in the same way, the peel can be reused as a by-product for the extraction of important enzymes in the pharmaceutical and food industry.