The combination of non-specific cytotoxic or immunosuppressive agents with bioactive natural substances as part of combination pharmacotherapy is an important process in modern medicine. Methotrexate (MTX) is a folic acid metabolism blocker that is used in treating various types of cancer and chronic autoimmune inflammatory diseases, like psoriasis and rheumatoid arthritis. However, it has limited efficacy due to strong off-target toxicity, rapid biological clearance, and the development of resistance to multiple drugs. Curcumin (CUR) is a non-polar polyphenol that has anticancer, anti-inflammatory, antioxidant, and chemosensitizing effects. CUR enhances the synergistic action of MTX and fights transport resistance, restoring the sensitivity of the affected cells and activating the Nrf2/ARE pathway, which helps to avoid MTX-induced liver toxicity, digestive system mucositis, and oxidative injury. Nevertheless, the clinical effectiveness of MTX and CUR combinations is limited by their disparate pharmacokinetic characteristics, low solubility in water, and rapid curcumin metabolism. Advanced drug delivery systems, such as liposomes, polymeric nanoparticles, solid lipid carriers, dendrimers and ointments containing liposomal gel were developed to tackle pharmacokinetic problems that arise due to those features. This review provides a comprehensive evaluation of the individual pharmacological properties of both MTX and CUR. It discusses the complexities of their molecular interactions, advances in drug delivery technologies including the use of liposomal and topical gel formulations, and the challenges of translating their findings into the real world.