In recent years, the issue of PM2.5-O3 compound pollution has become a significant global environmental concern. This study examines the spatial and temporal patterns of global PM2.5-O3 compound pollution and exposure risks, firstly at the global and urban scale, using spatial statistical regression, exposure risk assessment, and trend analyses based on the datasets of daily PM2.5 and surface O3 concentrations monitored in 120 cities around the world from 2019 to 2022. Additionally, on the basis of the common emission sources, spatial heterogeneity, interacting chemical mechanisms, and synergistic exposure risk levels between PM2.5 and O3 pollution, we proposed a synergistic PM2.5-O3 control framework for the joint control of PM2.5 and O3. The results indicated that: (1) Nearly 50% of cities worldwide were affected by PM2.5-O3 compound pollution, with China, South Korea, Japan, and India being the global hotspots for PM2.5-O3 compound pollution; (2) Cities with PM2.5-O3 compound pollution have exposure risk levels dominated by ST + ST (Stabilization) and ST + HR (High Risk). Exposure risk levels of compound pollution in developing countries are significantly higher than those in developed countries, with unequal exposure characteristics; (3) The selected cities showed significant positive spatial correlations between PM2.5 and O3 concentrations, which were consistent with the spatial distribution of the precursors NOx and VOCs; (4) During the study period, 52.5% of cities worldwide achieved synergistic reductions in annual average PM2.5 and O3 concentrations. The average PM2.5 concentration in these cities decreased by 13.97%, while the average O3 concentration decreased by 19.18%. This new solution offers the opportunity to construct intelligent and healthy cities in the upcoming low–carbon transition.