Climate change, as one of the main challenges of the current century, has extensive impacts on energy performance and thermal comfort of buildings. Given Iran’s climatic diversity and the lack of comprehensive research on redefining residential architectural design strategies based on future climate scenarios, this study aims to identify changes in thermal comfort and develop climate-responsive design guidelines for Iran’s five main climatic zones (Caspian, cold mountainous, hot-dry, hot semi-humid, and hot-humid) under the influence of climate change. For this purpose, 11 representative cities were selected from the mentioned zones, and current (2020) and future (2100) climate data were extracted using Meteonorm 8 software based on the moderate RCP4.5 scenario. Data analysis was conducted using Climate Consultant 6 software, employing ASHRAE-55 and Givoni thermal comfort charts. The findings indicate that the thermal comfort threshold will decrease in most studied cities by 2100, particularly in hot-humid (Bandar Lengeh with a 6.2% decrease) and Caspian (Ramsar with a 3.3% decrease) zones. The need for active cooling systems and solar shading devices increases across all zones, while the need for active heating decreases significantly. In hot-dry zones, two-stage evaporative coolers replace single-stage ones, and in hot-humid zones, cooling with dehumidification becomes the most important strategy. Based on the analyses, zone-specific design guidelines are proposed, including optimization of window dimensions and orientation, shading device type, appropriate materials, and use of semi-open spaces. The results of this study can serve as a basis for revising climate-responsive housing design standards in Iran, considering future climate changes.