Chalcone, a simple scaffold found in many naturally occurring compounds, has been widely used in medicinal chemistry due to its convenient synthesis and diverse biological activities. This review highlights recent advancements in chalcone as a privileged scaffold, focusing on its biosynthesis, synthetic methodologies, biological activities, and target exploration. Chalcones are synthesized through various methods, including the Claisen–Schmidt condensation, cross-coupling reactions (Suzuki, Heck, Wittig, Julia-Kocienski), Friedel–Crafts acylation, photo-Fries rearrangement, and one-pot synthesis from alcohols and ketones. The review also discusses the synthesis of cis-chalcones and the Michael reactions involving chalcones, such as Michael addition, cascade reactions, and epoxidation. Chalcones have shown potential in drug discovery and are being explored for their therapeutic applications, including cancer, inflammation, and diabetes. The review aims to provide a comprehensive overview of chalcone's role in medicinal chemistry, emphasizing its structural diversity and biological significance.Chalcone, a simple scaffold found in many naturally occurring compounds, has been widely used in medicinal chemistry due to its convenient synthesis and diverse biological activities. This review highlights recent advancements in chalcone as a privileged scaffold, focusing on its biosynthesis, synthetic methodologies, biological activities, and target exploration. Chalcones are synthesized through various methods, including the Claisen–Schmidt condensation, cross-coupling reactions (Suzuki, Heck, Wittig, Julia-Kocienski), Friedel–Crafts acylation, photo-Fries rearrangement, and one-pot synthesis from alcohols and ketones. The review also discusses the synthesis of cis-chalcones and the Michael reactions involving chalcones, such as Michael addition, cascade reactions, and epoxidation. Chalcones have shown potential in drug discovery and are being explored for their therapeutic applications, including cancer, inflammation, and diabetes. The review aims to provide a comprehensive overview of chalcone's role in medicinal chemistry, emphasizing its structural diversity and biological significance.