Due to intense population density and rapid economic development, ozone (O₃) pollution is serious in the Huaihe River Economic Belt (HREB) of China. Based on pollutant and meteorological observation data from 2015 to 2020, many interdisciplinary methods, e.g., Kernel Density Estimation (KDE), Standard Deviation Ellipse (SDE), and Multiple Linear Regression (MLR), were employed to investigate the spatio-temporal distribution and the meteorological driving force of O₃ in 27 cities in the HREB. The results revealed that the annual mass concentration of O3 increased in 2015~2018 and then decreased in 2019. The seasonal O₃ concentration displayed a bimodal structure, with highs in spring (122.3 μg/m³) and summer (134.7 μg/m³), and low in autumn (99.1 μg/m³) and winter (64.4 μg/m³). Spatially, the O₃ concentration in the northeastern HREB was higher than in the southwestern HREB. SDE analysis indicated that southeast Shangqiu (33.80°N-33.89°N, 116.33°E-116.40°E) was the center of gravity for O₃ concentrations in the HREB. The cities with severe O₃ pollution were clustered in the northern HREB, forming the high-high (HH) type, and those in the southern HREB with low O₃ concentrations forming the low-low (LL) type. Meteorological factors, including temperature, pressure, and sunshine duration, had a relatively significant impact on O₃ concentration. Based on the results of t h e MLR analysis, meteorological factors can explain 82.2%~18.2% (60.5% on average) of the O₃ variation in the HREB. The O₃ in the northern HREB was more affected by meteorological conditions than in the southern HREB.