The rise of drug‐resistant microbes necessitates the development of new antimicrobial agents. Increasing resistance among multidrug‐resistant microbes has spurred research efforts to overcome drug resistance through novel scaffolds and strategies. Chalcones, distinguished by their chemical structure of 1,3‐diphenylprop‐2‐en‐1‐one, have exhibited a multifaceted array of biological activities, prominently including antimicrobial and antiviral properties. Modifying the structure by adding substituent groups to the aromatic ring enhances potency, reduces toxicity, and expands pharmacological effects. This review highlights the potential of chalcones and analogues in preventing diseases affected by diverse antibiotic resistance genes, including viruses, bacteria, fungal spores, and Plasmodiidae. Our analysis underscores the fact that a multitude of chalcone compounds effectively obstruct various molecular targets pivotal in the development of antibiotic resistance, thus rendering bacteria vulnerable to conventional antibacterial agents and potentially obliterating resistance mechanisms. Certain chalcone compounds exhibit higher activity levels compared to traditional antibiotics like vancomycin and tetracycline. Additionally, Docking and SAR studies of chalcones summarize their role in developing novel drugs. Chalcones and their derivatives demonstrate promising broad‐spectrum antimicrobial activities. Investigating structure‐activity relationships (SAR) enhances our understanding of chalcone‐based drug design, enabling the development of more effective therapeutic interventions against the pressing global health challenge of antimicrobial resistance.