<p>Antimicrobial resistance (AMR) is a growing global health crisis traditionally attributed to the overuse and misuse of antibiotics. However, this correspondence aims to highlight the overlooked yet potentially significant role of non-antibiotic drugs (NADs)—which represent approximately 95% of the pharmaceutical market—in the emergence, persistence, and spread of AMR. We advocate for an&#xa0;urgent investigation into how commonly used NADs may promote AMR mechanisms even in environments devoid of antibiotics. This correspondence synthesizes and critically evaluates current scientific literature on the interaction between NADs and bacterial resistance pathways. The analysis focuses on molecular and environmental studies that reveal the ability of NADs—including nonsteroidal anti-inflammatories, lipid-lowering agents, β-blockers, and anticancer drugs—to induce genetic mutations, horizontal gene transfer (HGT), and plasmid-mediated antibiotic resistance. It incorporates experimental findings, wastewater surveillance data, and mechanistic studies that demonstrate NAD-induced reactive oxygen species (ROS) overproduction at clinically and environmentally relevant concentrations, increasing cell membrane permeability, and upregulate conjugal gene expression, facilitating antibiotic resistance genes (ARGs) dissemination. Clinical data further associate proton pump inhibitors, β-blockers, and antimetabolites with heightened risks of drug-resistant gram-negative infections in hospitalized patients. Particular attention is given to the clinical and environmental concentrations of these drugs and their potential role in resistance proliferation in both human and veterinary settings. This underscores an urgent need for systematic research into their resistance-promoting effects, updated regulatory frameworks, and public health strategies to mitigate unintended contributions to the antimicrobial resistance pandemic.</p> Graphical Abstract <p></p>