Background and Aim: p53 is a critical tumor suppressor protein responsible for regulating the cell cycle and inducing apoptosis. Mutations in the Materials and Methods: Curcumin and 20 derivatives were selected from PubChem for computational analysis. Their potential as p53 enhancers was assessed using Quantitative Structure-Activity Relationship (QSAR) analysis. Molecular docking was conducted to determine their binding affinities with wild-type and mutant p53 proteins, followed by molecular dynamics (MD) simulations to evaluate ligand-receptor stability. Pharmacokinetics and toxicity assessments were performed using predictive computational models to evaluate their drug-like properties. Results: QSAR analysis identified hexahydrocurcumin (probable activity [Pa]: 0.837) and tetrahydrocurcumin (Pa: 0.752) as the most potent p53 enhancers. Molecular docking revealed strong binding affinities for curcumin derivatives at key p53 binding residues, particularly through hydrogen bonds with His 273 of the R273H mutant. MD simulations demonstrated that curcumin, bisdemethoxycurcumin, and monodemethylcurcumin stabilized p53 mutant R273H, closely mimicking the structural stability of wild-type p53. Pharmacokinetic analysis indicated favorable absorption, distribution, metabolism, and excretion profiles for most derivatives, with low toxicity predicted for the majority. Conclusion: Curcumin and its derivatives exhibit dual functions as p53 enhancers and reactivators of the p53 mutant R273H. Hexahydrocurcumin and tetrahydrocurcumin emerged as promising compounds with strong bioactivity and favorable pharmacokinetic properties, suggesting their potential as anticancer agents. Further