Oral cancer is a global health concern, particularly because of its aggressive tissue invasion and metastases, holding 16th position on occurrence among all carcinoma worldwide. The aberrated transcription factor NF-κB1 influences development and spread of oral cancer, making it a potential therapeutic target. This study investigated the therapeutic potential of a few natural compounds from Artocarpus heterophyllus, Tinospora cordifolia, and Glycosmis pentaphylla in the treatment of oral cancer. Two FDA-approved drugs (5-fluorouracil, Docetaxel) and 16 natural compounds, including Artocarpin, Artocarpanone, Cycloartocarpin from Artocarpus heterophyllus; Berberine, Hydrastine, Magnoflorine, Palmatine Chloride, Tetrahydropalmatine from Tinospora cordifolia; and 5-Hydroxyarborinine, 5-Hydroxynoracronycine, 1-Hydroxy-3-methoxy-10-methyl-9-acridone, Des-N-methylacronycine, Des-N-methylnoracronycine, Kokusagenine, Noracronycin, Skimmianine from Glycosmis pentaphylla were examined using in-silico techniques. Among the 16 natural compounds studied, Hydrastine shown the highest binding energy (-6.87 kcal/mol) against NF-κB1, surpassing all other drugs, including the standards 5-fluorouracil (-4.04 kcal/mol) and docetaxel (-2.4 kcal/mol). Further molecular dynamics simulations and in-vitro experiments verified Hydrastine's exceptional anti-cancer activity. The results of in-vitro were well-aligned with the findings of in-silico, revealing considerable cytotoxicity, apoptosis induction, and cell cycle arrest. The findings revealed natural compounds' potential as safer, more effective alternatives to current cancer therapeutics, opening up new avenues for oral cancer treatment.