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Abstract COVID-19 vaccines played a critical role in reducing global health burden during the COVID-19 pandemic, but their rapid development required extraordinary effort. This study aims to evaluate their global return-on-investment (ROI) during the first year of the vaccination programme (8 December 2020-8 December 2021) to provide insights into the economic benefits relative to the costs of vaccine development, manufacturing, and delivery. Public health outcomes of COVID-19 vaccination, including life years and QALYs gained from averted death, infections, and hospitalisations, were estimated. Health benefits were converted to economic benefits using welfarist and extra-welfarist approaches. These benefits were compared to the costs of vaccine development, manufacturing, and delivery to estimate the ROI under both approaches. Probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on ROI estimates. Vaccine development and delivery cost $79.4 billion, but the health and economic benefits of vaccination were valued between $4.83 trillion–$37.8 trillion. High-income countries saw the greatest health benefits per-person vaccinated, and low-income countries gained the greatest non-health benefits per-person vaccinated, when expressed as a proportion of GDP per capita. This estimated ROIs of $59.8–$475 per dollar invested. ROIs ranged between $62.2–$442 across all sensitivity analyses for both approaches. Rapid COVID-19 vaccine development and delivery were an excellent investment. Vaccine development and equitable vaccine distribution globally should be prioritised before and during global health crises.