Enaminones are versatile synthetic intermediates characterized by the conjugation of an enamine and a carbonyl group. This unique structural motif allows them to participate in a wide range of heterocyclization reactions, affording diverse heteroaromatic scaffolds such as pyridines, pyrimidines, pyrazoles, thiazoles, and oxazoles. In recent years, enaminone-based heterocycles have attracted substantial interest due to their broad spectrum of biological activities, including antimicrobial, antiviral, anticancer, anti-inflammatory, and CNS-modulating properties. This review highlights recent advances (2010–2025) in the synthetic strategies of enaminone-derived heterocycles, reaction mechanisms, and structural modifications. Moreover, we provide a comprehensive overview of their biological activities with structure–activity relationship (SAR) insights and discuss future perspectives for drug discovery and medicinal chemistry.