Chalcone derivatives have garnered significant interest in antibacterial research due to their potential as potent therapeutic agents. This review analyzes various studies to evaluate the structure and activity of chalcone derivatives that enhance antibacterial potency. Using the PRISMA method, literature searches were conducted through various databases such as PubMed and ScienceDirect using keywords related to chalcone and antibacterial activity. The chalcone derivatives’ structure–activity relationship (SAR) indicated that molecular structure modification, such as the addition of electron-withdrawing groups such as chlorine and nitro and electron-donating groups such as methoxy, significantly affected the antibacterial activity. This effect is due to the electronic and lipophilicity changes, which enhance the interactions with bacterial cell membranes or targets. Additionally, the position of the substituents is also important because it affects their interactions with biological targets. The introduction of new nuclei, such as pyrazoline or sulfonamide, and their combination with prenyl or coumarin groups enhanced the antibacterial activity by balancing polarity and lipophilicity. An effective chalcone design should incorporate these properties to improve the efficacy against gram-negative and gram-positive bacteria. © 2025 Elsevier B.V.