The present study investigates the antioxidant and cytotoxic properties of natural phytochemicals and NSAIDs, focusing on their potential anticancer effects against selected cancer cell lines. Luteolin, a dietary flavonoid with known antioxidant and anticancer activities, and piroxicam, a Non-Steroidal Anti-Inflammatory Drug (NSAID) with reported anticancer potential, were examined both individually and in combination against MMP-9. Molecular docking revealed that the piroxicam–luteolin complex demonstrated stable interactions with key residues, including GLU241, ALA242, LEU243, TYR245, MET247, PRO245, HIS226, GLN227, ALA189, LEU188, LEU222, TYR248, and ARG249, with a binding energy of –6.89 kcal/mol, indicating favorable binding affinity. Antioxidant activity assays revealed that luteolin and piroxicam alone exhibited IC₅₀ values of 22.85 ± 0.080 μM and 20.512 ± 0.04 μM, respectively. Notably, their combination reduced the IC₅₀ to 10.89 ± 0.34 μM, suggesting a synergistic enhancement of antioxidant capacity. Similarly, MTT assays demonstrated that luteolin and piroxicam individually displayed cytotoxic effects with IC₅₀ values of 198.3 ± 0.088 μM and 175.5 ± 0.129 μM, while their combination yielded a significantly lower IC₅₀ of 73.3 ± 0.25 μM, confirming a synergistic effect in inhibiting cancer cell proliferation. Furthermore, intracellular ROS estimation revealed effective reduction in ROS levels by luteolin and piroxicam individually, with amplified effects observed upon their combined treatment. These findings indicate that the luteolin–piroxicam combination offers superior antioxidant and cytotoxic activity compared to either compound alone. Thus, this synergistic interaction highlights a promising strategy for developing safe, natural, and effective anticancer therapies, warranting further validation through in vivo studies.