<p>Chalcones are a subclass of flavonoids characterized by the presence of an α, β-unsaturated carbonyl system, and they have emerged as important scaffolds in medicinal chemistry because of their structural simplicity, ease of synthesis, and wide spectrum of pharmacological activities. They occur abundantly in nature and are reported to exhibit antioxidant, anti-inflammatory, antimicrobial, and particularly anticancer effects, making them attractive leads for therapeutic development. This review specifically highlights the most recent advances in chalcone-based anticancer research, with a focus on the structural features directly linked to enhanced cytotoxicity activity. Naturally occurring chalcones and their general pharmacological significance are briefly summarized to provide fundamental context. Classical methods, such as the Claisen–Schmidt condensation, remain the most widely used due to their simplicity and high yields, while modern catalytic, solvent-free, and green methodologies have expanded the diversity and efficiency of chalcone libraries. In parallel, structure–activity relationship (SAR) analyses are highlighted to illustrate how substituent effects, heterocyclic incorporation, and linker modifications influence activity profiles. Selected studies are discussed to demonstrate the relationship between structural design and cytotoxic responses across different cancer models. In the selected studies, aim to demonstrate how structural modifications can modulate cellular interactions, enhance therapeutic efficacy, and impact treatment outcomes across various cancer models. By integrating advances in synthesis with biological evaluation, this review emphasizes the versatility of chalcones and provides an updated framework for guiding rational design. The collective evidence underscores their promise as adaptable scaffolds for the development of next-generation anticancer agents.</p> Graphical abstract <p></p>