<p>The rising global concerns for antimicrobial resistance (AMR) urgently demands novel antimicrobial agents. Conventional antibiotics, which are purely based on organic moieties, are failing against multidrug-resistant (MDR) and pan-drug-resistant (PDR) pathogens, necessitating innovative therapeutic approaches. However, metallodrugs, compounds incorporating metal ions, have re-emerged as a promising class of antimicrobials. Historically used in medicine, their application declined with conventional antibiotics. However, metallodrugs offer unique chemical diversity, diverse mechanisms of action, and the ability to overcome established resistance pathways. This review explores their multifaceted actions, including membrane disruption, oxidative stress induction, and enzyme inhibition. Key metal ions like silver, copper, gold, gallium, bismuth, and ruthenium are highlighted for their antimicrobial applications and therapeutic potential. Advanced strategies for enhancing metallodrug efficacy include rational ligand design, combination therapies, nanotechnology-driven delivery systems, and photoactivation. While significant opportunities exist, challenges such as toxicity concerns, pharmacokinetic optimization, potential resistance mechanisms, and regulatory pathways must be addressed. This article provides a foundation for researchers and clinicians, emphasizing metallodrugs’ transformative potential in combating the AMR crisis and shaping infectious disease treatment.</p> Graphical Abstract <p></p>