Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by neuronal loss, attributed largely to oxidative stress and mitochondrial dysfunction. This study explores the synergistic neuroprotective effects of resveratrol and lithium chloride co-treatment, focusing on their impact on oxidative stress and autophagy via the p62/Keap1/Nrf2 signaling pathway. We focused on the multilevel evaluation of the monotherapy and co-treatment effects on neurons in terms of cellular and molecular features in vitro, such as metabolic activity, level of reactive oxygen/nitrogen species, total antioxidant capacity, DNA damage, level of ATP, neurite outgrowth, cell cycle and proteins level involved in intracellular signaling pathways, with particular emphasis on autophagy correlated with p62 protein. Additionally, we screened 92 genes involved in steps of protein aggregation, excitotoxicity, inflammation and oxidation. Studies have shown that co-treatment has stronger properties than monotherapy. Statistical analysis was conducted using one-way ANOVA followed by Dunnett’s post hoc test. The treatment indicated strong antioxidant properties, activation of autophagy, and the correlated apoptosis pathway via p62/Keap/Nrf2/ARE. Moreover, the therapy induced neurite outgrowth and eliminated DNA damage without disturbing the cell cycle. Finally, in the HT-22 cell line, therapy activated key genes involved in cell signaling and inflammation. In contrast, in SH-SY5Y cells, therapy engaged genes related to proteolysis, cell cycle regulation, protein kinase signaling, and lipid metabolism. These findings underscore resveratrol and lithium chloride co-treatment as a promising therapeutic strategy for mitigating oxidative damage and enhancing neuroprotection in PD. Relying on natural compounds, this combination could serve as a preventive strategy for the elderly.