Dihydropyrimidinones (DHPMs) is an main type of heterocyclic compounds whih shows biological activities. This review/article focuses on the synthetic strategies employed for the construction of DHPM frameworks and highlights their bioactivity profiles across various pharmacological targets. Several efficient synthetic protocols, including classical Biginelli multicomponent reactions, as well as modern catalytic and green chemistry approaches, have been explored to access DHPM derivatives with structural diversity and high yields. Structural modification of the DHPM core has led to compounds exhibiting antimicrobial, antiviral, anticancer, anti-inflammatory, calcium channel-blocking, and enzyme inhibitory activities. The structure–activity relationship (SAR) analysis indicates that substitutions on the dihydropyrimidinone nucleus significantly influence potency and selectivity, enabling rational design of derivatives with enhanced bio efficacy. In addition, the integration of DHPM scaffolds with other pharmacophores has yielded hybrid molecules with synergistic therapeutic effects. Overall, the versatile synthetic accessibility and promising bioactivity of DHPM derivatives underscore their significant potential in drug discovery and medicinal chemistry.