The development of effective emissions control policies that are beneficial to both climate and air quality requires a detailed understanding of all the feedbacks in the atmospheric composition and climate system. We perform sensitivity studies with a global atmospheric composition-climate model to assess the impact of aerosols on tropospheric chemistry through their modification on clouds, aerosol-cloud interactions (ACI). The model includes coupling between both tropospheric gas-phase and aerosol chemistry and aerosols and liquid-phase clouds. We investigate past impacts from preindustrial (PI) to present day (PD) and future impacts from PD to 2050 (for the moderate IPCC A1B scenario) that embrace a wide spectrum of precursor emission changes and consequential ACI. The aerosol indirect effect (AIE) is estimated to be −2.0 Wm−2 for PD-PI and −0.6 Wm−2 for 2050-PD, at the high end of current estimates. Inclusion of ACI substantially impacts changes in global mean methane lifetime across both time periods, enhancing the past and future increases by 10% and 30%, respectively. In regions where pollution emissions increase, inclusion of ACI leads to 20% enhancements in in-cloud sulfate production and ~10% enhancements in sulfate wet deposition that is displaced away from the immediate source regions. The enhanced in-cloud sulfate formation leads to larger increases in surface sulfate across polluted regions (~10–30%). Nitric acid wet deposition is dampened by 15–20% across the industrialized regions due to ACI allowing additional re-release of reactive nitrogen that contributes to 1–2 ppbv increases in surface ozone in outflow regions. Our model findings indicate that ACI must be considered in studies of methane trends and projections of future changes to particulate matter air quality.