Background <p>Chlorhexidine, a well-established antiseptic in systemic medicine and dentistry, has long been overlooked in ophthalmology outside its role in Acanthamoeba keratitis. However, recent evidence supports its potential as an effective adjunct or alternative agent in multidrug-resistant (MDR) bacterial keratitis, where treatment options remain limited and therapeutic challenges are escalating. This review aims to revisit ocular use of chlorhexidine.</p> Methods <p>A comprehensive search was performed in the PubMed database using combinations of the following keywords: “chlorhexidine”, “keratitis”, “Acanthamoeba keratitis”, “fungal keratitis”, “bacterial keratitis”, “ocularinfections”, and “antimicrobial resistance”. Studies relevant to the ophthalmological use of chlorhexidine, particularlyin the context of keratitis and antimicrobial resistance, were utilized.</p> Results <p>The results revealed chlorhexidine's antimicrobial mechanisms, ocular formulations, and clinical applications, while highlighting emerging evidence from case reports, retrospective analyses, and in vitro studies that suggest potential activity against MDR ocular pathogens, including extended spectrum beta lactamase (ESBL) producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), and carbapenem-resistant Pseudomonas spp.</p> Conclusions <p>As the threat of antimicrobial resistance rises globally, chlorhexidine merits renewed attention and clinical evaluation within ophthalmology, particularly as a viable and accessible therapeutic option in resistant infections. Although current evidence is limited to preclinical studies and case reports, chlorhexidine shows potential efficacy in MDR and may warrant further investigation in well-designed clinical trials.</p>