<p>The<?tk 4?> persistent challenge of tumor resistance undermines the efficacy of current chemotherapeutic regimens. Coumarins, naturally occurring benzopyrone derivatives, have long been recognized for their wide-ranging pharmacological potential, particularly their anticancer activities. However, single-target agents often fail to sustain long-term therapeutic success due to adaptive cellular mechanisms. This review aims to explore the rational design and biological significance of hybrid coumarins as multi-target anticancer agents capable of overcoming tumor resistance through synergistic molecular mechanisms. An integrative literature analysis was conducted, encompassing experimental studies, in vitro and in vivo evaluations, and clinical findings related to hybrid coumarin derivatives. Emphasis was placed on their structural design, synthesis, mechanistic pathways, and pharmacokinetic behavior. Hybridization of coumarins with diverse pharmacophores, including heterocycles, amides, and natural scaffolds, enhances cytotoxic potency and bioavailability while reducing toxicity. These hybrids modulate multiple oncogenic pathways, such as apoptosis, angiogenesis, and efflux pump inhibition, demonstrating broad efficacy across resistant cancer cell lines. In vivo models corroborate their tumor-suppressive effects and improved pharmacodynamic profiles. Hybrid coumarins represent a promising frontier in medicinal oncology, merging natural-product chemistry with modern drug design to achieve multi-target activity. Their ability to simultaneously interfere with several resistance mechanisms highlights their translational potential as next-generation anticancer candidates. Continued research integrating computational modeling, nanodelivery systems, and personalized oncology could expedite their clinical adoption.</p> Graphical Abstract <p></p>