Propolis is the extract of a resinous compound that protects plants from both cold and microorganism attack and has gained a strong and sticky property because it is transformed after being collected by honey bees. Up to date, many studies have shown that propolis exhibited various beneficial biological activities, such as antifungal, antibacterial, antiviral, antioxidant, antimutagenic, and antitumor effects. Recent reports propounded the in vitro and in vivo neuroprotective effect of propolis; however, the exact molecular genetic mechanisms are still unclear. Therefore, we aimed to investigate the toxicogenomic and beneficial properties, including cytotoxic, antioxidant, apoptotic/necrotic as well as genotoxic effects of propolis (1.56–200 µg/ml) on differentiated SH-SY5Y neuronal cells. Additionally, microarray analysis was conducted on cell cultures following propolis application to explore gene differentiation. Differentially expressed genes were further analyzed using string software to characterize protein–protein interactions between gene pathways. Our results revealed that propolis applications could not have a prominent effect on cell viability even at concentrations up to 200 µg/ml. The highest propolis concentration induced apoptotic rather than necrotic cell death. The alterations in gene expression profiles, including CYP26A1, DHRS2, DHRS3, DYNC1I1, IGF2, ITGA4, SVIL, TGFβ1, and TGM2 could participate in the neuroprotective effects of propolis. In conclusion, propolis supplementation exerted remarkable advantageous; thus, it may offer great potential as a natural component in the prevention and treatment of neurodegenerative disorders. Whole-genome gene expression pattern following propolis application was investigated for the first time in neuronal cell culture to fill a gap in the literature about propolis toxicogenomics. Practical applications: Propolis is a very rich product in terms of benefits. In addition to its antibacterial, antiviral, antifungal, and anti-inflammatory content, it is known to have preventive and therapeutic properties for many different ailments. On the other hand, molecular mechanisms of propolis on gene expression differentiations haven't been investigated until now. Moreover, gene expression pattern is vital for all living organisms to maintain homeostasis. Thus, we conduct an experiment series for analyzing gene expression differentiation effects on neuronal cells to understand beneficial properties of propolis. Hence, it could be possible to comment on the use of propolis as a nutritional factor and beneficial diet.