To investigate the spatial-temporal variations and health impacts of O₃ (ozone) in the Central Plains Urban Agglomeration, China (CP-UA), multiple and transdisciplinary methods were employed to analyze the collected millions of O₃ concentrations data. The results showed that the annual average concentration of O₃ in the CP-UA reduced by 19.7% from 2017 to 2020. O₃ monthly concentrations exhibited a multimodal structure and a feature of “high in summer and winter, low in spring and autumn”. In spatial distribution, the main distribution of O₃ concentration was aligned in the northwest-southeast direction in the CP-UA. O₃ concentrations displayed positive spatial autocorrelations. The most polluted cities were distributed in northern CP-UA, forming a high-high (HH) agglomeration of O₃ concentrations. Cities in southern CP-UA had low O₃ concentrations, forming a low–low (LL) agglomeration pattern. It was estimated that the premature mortalities attributed to O₃ for respiratory disease in warm months were 15, 960 per year. The premature mortalities decreased by 28.7% in 2020 compared to 2017. The rescaled range analysis suggested a declining trend of O₃ concentrations and premature mortalities in the CP-UA.