Alzheimer’s disease (AD), typically characterized by the accumulation of the misfolded proteins Amyloid beta (Aβ1-42) and hyperphosphorylation of Tau (P-Tau), is the most common neurodegenerative disease. Although there is currently no cure, research with rodent models has found targeting the signaling pathways involved in reactive oxygen species (ROS) or the unfolded protein response (UPR) can diminish the toxic effects of AD (e.g., behavioral deficits, glial inflammation, and proteotoxicity). For this study, we hypothesized that treatment combining Cannabidiol (CBD) and Trazodone (TRA), would better mitigate neuronal dysfunction and extend the lifespan of nematodes engineered to aggregate toxic misfolded proteins. CBD and TRA have been individually found to diminish the deleterious effects of proteotoxicity in both in vivo and in vitro studies. The organisms utilized in the study included two strains of C. elegans genetically modified to express two pathological proteins of AD. Our experiments revealed that the motility and lifespan of C. elegans with proteotoxicity of either Aβ1-42 or P-tau were significantly improved by treatment with CBD and TRA in combination. We also confirmed aspects of existing research on the efficacy of CBD and TRA individually. Our data suggest that these benefits are seen with full-life, middle-age, and late-stage rescue utilizing CBD and TRA. These findings suggest the need for future experimentation incorporating CBD and TRA in treatment regiments in higher organisms, including neurodegenerative rodent models and aging canines with cognitive decline.