<p>Royal jelly (RJ) is a natural product that reduces toxic effects and has anti-proliferative effects. The aim of the study is to increase the anticancer effect of Paclitaxel (PAX), which is used in cancer treatment, and to reduce its toxic effect with RJ in oral squamous carcinoma cells. Cytotoxicity tests of RJ and PAX substances were tested on healthy gingival HGF cells and their anti-proliferative effects on UPCI-SCC-131 cells with real-time cell analyzer (xCELLigence RTCA). Their anti-migratory properties were observed with wound healing assay. Glycolysis stress test was performed with Seahorse XFe24 to measure the glycolytic capacity. Total RNA-seq libraries were created and sequenced with NovaSeq 6000. Transcriptome profiles were created with bioinformatic analyses and functional enrichment analyses were performed. Results demonstrate that both RJ and PAX exhibit significant anti-proliferative effects against oral squamous cell carcinoma cells, as quantified by real-time cell analysis. Notably, RJ co-treatment mitigated PAX-induced cytotoxicity in healthy human gingival fibroblasts, suggesting a protective role against chemotherapy-associated toxicity. While both compounds inhibited cancer cell proliferation, PAX particularly displayed potent anti-migratory properties in wound healing assays, significantly impairing OSCC cell motility. Metabolic profiling revealed that the RJ-PAX combination therapy substantially reduced glycolytic capacity in OSCC cells, indicating disruption of their energy metabolism. Transcriptomic analysis identified downregulation of critical cell cycle regulators (<i>MCM2, CDC25A, CCNE2</i>) and DNA replication factors (<i>RFC2, PCNA</i>), along with modulation of MYC and E2F pathways, providing insights into the observed anti-cancer effects</p>