Childhood mortality remains a major public health challenge in low-income and middle-income countries, particularly in sub-Saharan Africa, despite major advances in universal sanitation and immunisations. Mass drug administration (MDA) of azithromycin, a broad-spectrum antibiotic, has shown promise in reducing under-5 mortality in high-risk regions, although its mechanism of protection remains largely unknown. In this Personal View, we analyse current evidence, potential effect of MDA on antimicrobial resistance, and relevant ethical principles, and propose priorities for future public health interventions. Our review of key randomised controlled trials revealed highly variable outcomes of azithromycin MDA differing by participants’ age, geographical location, comorbidities, coinfections, and concurrent therapies. Intermittent use of azithromycin has been linked to rising macrolide resistance in several pathogens, spillover effects in untreated populations, and ecological disruptions. Ethical concerns, including informed consent and allocation of limited resources, require careful consideration. We propose a multifaceted approach including investments in water, sanitation, and hygiene infrastructure, vaccination programmes, and robust antimicrobial resistance surveillance. Policy makers and global health stakeholders must prioritise context-specific, evidence-based strategies that strengthen local capacity, improve community engagement, and implement robust monitoring systems to ensure that the potential benefits of MDA are sustained and do not imperil public health.