<p>Topical corticosteroid (TC) and antimicrobial combinations have been widely used for skin, eye, ear, and nasal diseases. These combinations provide therapeutic benefits by addressing both inflammatory and infectious components, thereby improving patient compliance and outcomes. Especially, in atopic dermatitis and bacterial keratitis, TC and antimicrobial combinations have demonstrated effectiveness in reducing inflammation and improving clinical outcomes. However, their role in other conditions such as fungal keratitis and chronic rhinosinusitis remains controversial, requiring further research. Despite their advantages, irrational and excessive use, particularly in the resource-limited settings where they are available over the counter, raises concerns about adverse effects and the potential for antimicrobial resistance (AMR). Current evidence suggests that short-term, rational use of these combinations does not significantly contribute to AMR. However, prolonged misuse can exacerbate complications. While AMR concerns are primarily associated with the misuse of antimicrobials alone, the availability of TC and antimicrobial combinations without prescriptions, especially in resource-limited countries, amplifies this risk. Remarkably, studies show no convincing evidence that these combinations increase the risk of infections or inhibit the therapeutic effects of antimicrobials, provided they are prescribed rationally. To maximize therapeutic outcomes while minimizing risks, prescribers must emphasize rational usage, guided by clinical and bacteriological evidence. Stricter regulations, alongside improved health education, are crucial to mitigating misuse. This review highlights the need for further research to clarify long-term effects on AMR and optimize usage guidelines for TC and antimicrobial combinations.</p>