AIM: This research aimed to investigate the effect of 6-Paradol on sorafenib cytotoxicity in colorectal cancer (CRC) cell lines (HT-29, HCT-116, LS-174T, CaCo-2) through its effects on cellular processes. BACKGROUND: CRC, which ranks as the third most prevalent cancer, arises in the colon or rectum due to a multifaceted interplay of dietary, lifestyle, genetic, and age-related factors. Sorafenib (multikinase inhibitor), a drug targeting multiple cancer signals, shows promise against liver, thyroid, and kidney tumors but faces resistance in CRC. 6-Paradol (Zingiberaceae), a natural compound, offers the potential for overcoming this resistance. OBJECTIVE: The current study investigates whether 6-paradol potentiates sorafenib's anti-cancer activity in CRC cells by promoting increased drug entrapment, uptake, and metabolism. METHOD: Sulpharodamine B assay, caspase-3 activity, PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity were assessed for Cytotoxicity using CRC cell lines (HT-29, HCT-116, LS-174T, CaCo-2). RESULT: Sorafenib showed potent cytotoxicity across CRC cell lines (IC CONCLUSION: In conclusion, 6-Paradol marked elevation in sorafenib's cytotoxic profile by influencing its cellular uptake and metabolism. Future research should expand in vitro studies to diverse cell lines, conducting in vivo elucidating underlying mechanisms and rigorously evaluating safety and toxicity.