OBJECTIVES: In mid-2020, the Ghana Health Service introduced Zipline's aerial logistics (centralized storage and delivery by drones) in the Western North Region to enhance health supply chain resilience. This intervention led to improved vaccination coverage in high-utilization districts. This study assessed the cost-effectiveness of aerial logistics as an intervention to improve immunization coverage. METHODS: An attack rate model, adjusted for vaccination coverage and vaccine efficacy, was used to estimate disease incidence among vaccinated and unvaccinated populations, focusing on 17 022 infants. Incremental cost-effectiveness ratios of US dollar per averted disability-adjusted life-year (DALY) were evaluated from societal and government perspectives, using real-world operations data. Probabilistic sensitivity analysis was performed using Monte Carlo simulations. RESULTS: In 2021, aerial logistics averted 688 disease cases. Incremental cost-effectiveness ratios were 1 and 8 per averted DALY from the societal and government perspectives, respectively. The intervention was cost-saving when at least 20% of vaccines delivered by aerial logistics replaced those that would have been delivered by ground transportation, with potential government savings of up to 50 per averted DALY. Sensitivity analysis confirmed the robustness of these findings. CONCLUSIONS: Under conservative assumptions, aerial logistics was a highly cost-effective intervention to increase immunization coverage. The intervention was cost-saving even with low levels of replacement of traditional last mile delivery. These findings support expanding aerial logistics within the national immunization program and have significant implications for other low- and middle-income countries seeking cost-effective health supply chain solutions.