PM2.5 concentrations have dramatically reduced in key regions of China during the period 2013–2017, while O3 has increased. Hence there is an urgent demand to develop a synergetic regional PM2.5 and O3 control strategy. This study develops an emission-to-concentration response surface model and proposes a synergetic pathway for PM2.5 and O3 control in the Yangtze River Delta (YRD) based on the framework of the Air Benefit and Cost and Attainment Assessment System (ABaCAS). Results suggest that the regional emissions of NOx, SO2, NH3, VOCs (volatile organic compounds) and primary PM2.5 should be reduced by 18%, 23%, 14%, 17% and 33% compared with 2017 to achieve 25% and 5% decreases of PM2.5 and O3 in 2025, and that the emission reduction ratios will need to be 50%, 26%, 28%, 28% and 55% to attain the National Ambient Air Quality Standard. To effectively reduce the O3 pollution in the central and eastern YRD, VOCs controls need to be strengthened to reduce O3 by 5%, and then NOx reduction should be accelerated for air quality attainment. Meanwhile, control of primary PM2.5 emissions shall be prioritized to address the severe PM2.5 pollution in the northern YRD. For most cities in the YRD, the VOCs emission reduction ratio should be higher than that for NOx in Spring and Autumn. NOx control should be increased in summer rather than winter when a strong VOC-limited regime occurs. Besides, regarding the emission control of industrial processes, on-road vehicle and residential sources shall be prioritized and the joint control area should be enlarged to include Shandong, Jiangxi and Hubei Province for effective O3 control.