Exposure to hydrogen peroxide (H₂O₂) is a well-established method for inducing oxidative stress (OS) in cellular models, mainly through the generation of reactive oxygen species (ROS). There is evidence in the literature of a strong association between the production of free radicals and neurodegenerative diseases. Plant-derived natural products have been considered important sources of biologically active compounds, most of which possess strong antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, and anti-viral properties. There are limited studies in the literature on the neuroprotective potentials of phytoextracts from two botanicals with well-known health benefits, Sutherlandia frutescens (SF) and Carpobrotus edulis (CE), hence this study investigated the possibility of the aqueous extracts (SF_e and CE_e) of both these botanicals to attenuate possible hydrogen peroxide (H₂O₂)-induced physiochemical and bioenergetic damage in SH-SY5Y cells. The cells were pre-treated for 24 hours with the maximum non-toxic concentrations (MNTC) of SF_e and CE_e respectively, after which 250 μM of H₂O₂ was added, and the cells incubated for 3 hours followed by assays to evaluate cell viability, caspase-9 activity, nitric oxide activity, intracellular calcium, and ROS levels, superoxide dismutase and catalase activity, as well as mitochondrial membrane permeability. The results showed that the cellular dysfunction caused by H₂O₂ in the SH-SY5Y cells was significantly attenuated by pre-treatment with both SF_e and CE_e. The observed benefits of these treatments could be attributed to the synergistic effects of the phytocompounds in the phytoextracts. Further in vitro and in vivo investigations of these compounds are recommended.