Global climate change associated with increasing temperature and unreliable rainfall events will have consequences for crop production. Therefore, strategizing crop management gained the attention of crop scientists to curtail the adverse impacts of climate change on crop production. However, the projected effects of climate change on wheat may vary in different cropping systems as wheat production is reported to be significantly impacted by future climate change in major cropping systems worldwide. In the present study, ten experiments were conducted under irrigated (2007–2013) and rainfed (2010–2014) cropping systems of Pakistan to quantify the interactive impacts of future climate change (CO₂, temperature, and rainfall) on wheat phenology, grain yield, crop evapotranspiration (ET_c), and water use efficiency (WUE) using the DSSAT-CERES-Wheat. The DSSAT-CERES-Wheat was executed using 17 Global Climate Models (GCMs) and four Representative Concentration Pathways (RCPs; 2.6, 4.5, 6.0, and 8.5) to forecast the climate projections for 2030, 2050, and 2090. The average temperature at both sites will increase by 1.3, 1.9, 1.9, and 2.9 ℃ under RCP 2.6, 4.5, 6.0, and 8.5. The simulated output varies among GCMs, RCPs, CO₂ concentration, and future periods. A general reduction in wheat phenology, grain yield, ET_c, and WUE was anticipated. However, higher CO₂ concentration and early maturity improved the WUE of wheat under irrigated and rainfed conditions. Nevertheless, this gain in WUE was at the cost of a relatively higher yield loss. Wheat yield is expected to decline by 2–19% and 9–30% under irrigated and rainfed conditions, respectively by aggregating the simulated future climate change impacts across GCMs and RCPs. Adaptation strategies to mitigate the climate change impacts on wheat production in irrigated and rainfed areas will be required. Our findings will serve as a foundation for designing future climate change adaptation strategies to sustain wheat production in Pakistan's irrigated and rainfed cropping systems.