Chalcones, α,β-unsaturated ketone linking two aromatic moieties gained noticeable attention in the medicinal chemistry area. Chalcone-scaffold construction has proceeded via verified chemical synthetic strategies, including condensation, coupling, olefination, acylation, reductive annulation, one-pot, and Fries' rearrangement methods. Specific approaches have assisted chalcone combinations using microwave radiation and ultrasound waves to enhance synthetic conditions and amplify yields. Recently, chalcones have been investigated extensively as core structures in potent bioactive hybrids such as anticancer, antimicrobial, and others. In addition, chalcones serve as parent structures for synthesizing several bioactive heterocyclic derivatives comprising five-membered and six-membered rings. This review will discuss recent applications of chalcones' synthetic strategies, physical and chemical characters, biological activities, and chemical derivatization.