Background/Objectives:Pereskia aculeata and Pereskia grandifolia belong to the Cactaceae family, despite their foliar and woody stem characteristics. Both species are commonly known as Ora-pro-nóbis (derived from Latin, meaning “pray for us”), a name rooted in their historical use in colonial Brazil due to their nutritional value, particularly P. aculeata, which is frequently described as a high-protein food source. The goal of the present study was to compare these species based on phytochemical composition and antioxidant capacity. Methods: Both species were investigated for their chemical antioxidant properties (DPPH and phosphomolybdenum complex) and cellular anti-ROS activity using the CACO-2 cell line. A comprehensive phytochemical analysis was performed using LC-MS and GC-MS. Results: P. aculeata exhibited a more abundant content of phenolics and flavonoids, with greater structural variability in phenolic compounds and glycosylated flavonoids than P. grandifolia. Still, P. aculeata showed a more potent chemical antioxidant effect. By contrast, in P. grandifolia, a series of novel saponins was now discovered and characterized. In addition, the compounds from this species exhibited a greater cellular antioxidant activity than those of P. aculeata. Tryptophan-derived alkaloids, such as abrine (N-methyltryptophan), were present in both species, but hypaphorine only in P. aculeata. Conclusions: Both species of Pereskia exhibit potential health benefits, including distinct antioxidant activity, among other unexplored effects, given their significant variability in phytochemicals. These differences could be investigated in greater depth using combined LC-MS and GC-MS, thereby enabling more confident structural investigations of these natural compounds.