Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and the relationship between oxidative stress and PD is complex and multifaceted. Recent research has demonstrated that protocatechuic acid (PCA) and karanjin (KJN) can mitigate oxidative stress and may offer neuroprotective benefits in PD. PCA has also been reported to work synergistically with various other drugs or phytoconstituents, such as PCA and ginkgolide B in neuroprotection, PCA with catechin and vanillic acid against bacterial adhesion, and PCA with 5-fluorouracil in cancer therapy. 1-methyl-4-phenylpyridinium (MPP+) was used to induce PD in SH-SY5Y cells, leading to increased intracellular reactive oxygen species (ROS) generation and significant cell damage. Treatments with KJN and PCA reduced MPP⁺-induced cell damage by decreasing ROS generation. KJN and PCA enhanced NRF2 mRNA and heme oxygenase-1 (HO-1) expression. However, the HO-1 inhibitor zinc protoporphyrin diminished the antioxidant and neuroprotective benefits of KJN and PCA. NRF2 knockdown decreased HO-1 expression and the neuroprotective effects of KJN and PCA. The phosphoinositide 3-kinase/Akt inhibitor LY294002 eliminated the impact of KJN and PCA on NRF2-HO-1 expression, cell survival, lactate dehydrogenase release, and ROS production in MPP⁺-stimulated SH-SY5Y cells, but not the MAPK pathway inhibitors (PD98059, SP600125, and SB203580). These findings suggest that the neuroprotective effects of KJN and PCA in SH-SY5Y cells are linked to NRF2-mediated HO-1 expression, specifically through the PI3K/Akt pathway.