Mexico is one of the main diversification centers of cacti in the world, with more than 500 endemic species, most of which remain nutritionally and functionally uncharacterized. The columnar cacti of the genus Pachycereus comprise five underutilized endemic Mexican species, whose nutraceutical properties have only been studied in the P. weberi species. Therefore, this study aimed to evaluate the nutritional quality and bioactive properties of etcho (P. pecten-aboriginum) and giant cardon (P. pringlei) fruit. The physical, chemical, and nutritional composition of etcho and giant cardon fruits were characterized, as well as the profile and content of bioactive compounds, antioxidant activity (ABTS•+ and DPPH•), and antiproliferative capacity in cervical (HeLa) and breast cancer (MDA-MB-231, MCF-7, and T-47D) cell lines. Our results suggest that etcho and giant cardon fruits are rich sources of essential nutrients and bioactive phytochemicals (including K, Mg, P, dietary fiber, polyphenolic compounds, vitamin C, betalains, and myo-inositol) with antioxidant and anticancer potential by inhibiting the proliferation of all evaluated cell lines with IC50 values in the range of 198 to 287µg of gallic acid equivalents/mL. Therefore, etcho and giant cardon fruits could be used for nutraceutical purposes, and their consumption could promote health benefits.