Abstract <p>Coumarins are a versatile class of naturally occurring benzopyrone derivatives that have attracted increasing interest due to their broad pharmacological activities and promising anticancer potential. Their structural diversity enables modulation of key molecular pathways involved in tumor initiation, progression, and therapeutic resistance. This review summarizes advances over the past two decades, highlighting the integration of coumarin chemistry with cancer pharmacology and genetic regulation. Evidence from preclinical studies and emerging clinical data demonstrates that coumarin derivatives exert multifaceted anticancer effects, including induction of apoptosis, suppression of angiogenesis and metastasis, and reduction of oxidative stress. Importantly, several coumarins influence major oncogenic and tumor suppressor pathways such as p53, NF-κB, PI3K/Akt, and MAPK, supporting their potential role in targeted molecular intervention. Structure–activity investigations further reveal that selective substitutions on the coumarin scaffold can enhance DNA interaction, modulate enzyme inhibition, and improve affinity toward gene regulatory proteins. In addition, combining coumarins with established chemotherapeutics may enhance anticancer efficacy while minimizing toxicity. Overall, coumarin derivatives represent a promising platform for developing next-generation anticancer agents. Continued research, including rational design strategies and translational validation, is warranted to accelerate their transition toward personalized oncology applications.</p> Graphical Abstract <p></p>