INTRODUCTION: Despite effective preventative measures, rheumatic heart disease (RHD) continues to be a significant contributor to cardiovascular morbidity and mortality in low- and middle- income nations. Azithromycin (AZM) has drawn attention due to its antibacterial, antiinflammatory, and immunomodulatory properties that are pertinent to the pathophysiology of RHD. In the context of RHD and acute rheumatic fever (ARF), this narrative review synthesises mechanistic, preclinical, and limited clinical information on AZM, differentiating between evidence-based therapeutic application and hypothesis-generating biological plausibility. METHODS: Through May 2025, a systematic narrative literature search was conducted in PubMed, Scopus, and Google Scholar to find research on AZM's immunoregulatory effects, modulation of inflammatory pathways, and antibacterial activity. Key findings were summarized using conceptual synthesis and reference screening. RESULTS: According to experimental research, AZM reduces inflammatory mediators like MUC5AC, MMP-9, and IL-8 by influencing molecular pathways like MAPK, NF-κB, and AP-1. These processes may be important for reducing immune-mediated tissue damage in RHD. Clinical data is still limited and inconsistent, nevertheless. Benzathine penicillin G (BPG) is still the best option for secondary prophylaxis, according to comparative research; AZM only exhibits theoretical or situationspecific benefits (e.g., oral dose, patient adherence, or allergy scenarios). DISCUSSION: Research indicates that azithromycin's three distinct mechanisms-antibacterial, antiinflammatory, and immunomodulatory-may provide a tactical edge in the treatment of RHD, particularly in situations where conventional therapies are ineffective. A wider use in secondary prevention and possible disease modification is suggested by its effects on important inflammatory mediators and signalling pathways. However, pharmacogenomic research and long-term clinical trials are necessary to confirm its effectiveness and customise therapies. CONCLUSIONS: Rather than being a proven treatment for RHD prophylaxis, AZM should be considered an experimental supplement. Although well-designed, context-specific randomised trials integrating safety, resistance surveillance, and cost-effectiveness assessments are necessary to translate their molecular effects into therapeutic benefit, they do offer useful information for idea formulation. AZM may only be taken into consideration in situations of penicillin intolerance or as part of an implementation or feasibility study in places with limited resources.