Reducing air pollutants and CO2 emissions from energy utilization is crucial for achieving the dual objectives of clean air and carbon neutrality in China. Thus, an optimized health-oriented strategy is urgently needed. Herein, by coupling a CO2 and air pollutants emission inventory with response surface models for PM2.5-associated mortality, we shed light on the effectiveness of protecting human health and co-CO2 benefit from reducing fuel-related emissions and generate a health-oriented strategy for the Yangtze River Delta (YRD). Results reveal that oil consumption is the primary contributor to fuel-related PM2.5 pollution and premature deaths in the YRD. Significantly, curtailing fuel consumption in transportation is the most effective measure to alleviate the fuel-related PM2.5 health impact, which also has the greatest cobenefits for CO2 emission reduction on a regional scale. Reducing fuel consumption will achieve substantial health improvements especially in eastern YRD, with nonroad vehicle emission reductions being particularly impactful for health protection, while on-road vehicles present the greatest potential for CO2 reductions. Scenario analysis confirms the importance of mitigating oil consumption in the transportation sector in addressing PM2.5 pollution and climate change.