Cancer therapy continues to face major challenges due to nonspecific drug distribution, systemic toxicity, and the emergence of drug resistance. Repurposing established drugs in combination with bioactive natural compounds and delivering them through nanocarriers represents a promising strategy to overcome these limitations. The present study focuses on the formulation, characterization, and combined efficacy evaluation of metformin hydrochloride and quinic acid–loaded niosomes for enhanced anticancer activity. Metformin, a widely used antidiabetic agent, exhibits anticancer effects through AMPK activation, mTOR inhibition, and metabolic reprogramming, while quinic acid, a natural polyphenolic compound, possesses antioxidant, anti-inflammatory, and pro-apoptotic properties. Co-encapsulation of these agents in niosomal nanocarriers was undertaken to improve bioavailability, ensure synchronized delivery, and achieve synergistic therapeutic effects. The niosomes were prepared using suitable non-ionic surfactants and cholesterol and evaluated for physicochemical characteristics, including particle size, polydispersity index, zeta potential, entrapment efficiency, drug content, and in-vitro drug release. Morphological analysis confirmed the formation of uniformly distributed nanosized vesicles. In-vitro cytotoxicity studies demonstrated that the co-loaded niosomes exhibited significantly enhanced anticancer activity compared to individual drugs and their free combination, indicating synergistic efficacy. Overall, the findings suggest that metformin and quinic acid co-loaded niosomes offer a promising, cost-effective, and multi-targeted nanotherapeutic approach for cancer management with potential for further translational development.