Cooling buildings in urban areas with hot-arid climate put huge loads on the energy system. There is an increasing trend in urban energy studies to recognize the urban design variables and parameters associated with the energy performance of buildings. In this work, a novel approach is introduced to investigate the impacts of urban morphology on cooling load reduction and enhancing ventilation potential by studying a high-rise building (target building), surrounded by different urban configurations, during six warm months of the year in Tehran at four major sections including: (1) generating 1600 urban case studies considering three parameters (Urban Density, Urban Building Form, and Urban Pattern) and modelling the urban morphology of Tehran based on a technique namely “Building Modular Cells”, (2) validation study of CFD simulation of the wind flow around buildings, (3) calculating the average cooling load and wind flow at the rooftop of the target building, and (4) investigating sixteen best urban configurations with the lowest cooling load and highest ventilation potential. Results indicate that urban morphology has a notable impact on the energy consumption of buildings, decreasing cooling load and increasing ventilation potential more than 10% and 15% respectively, compared to the typical cases. This work also proposes design solutions for architects and urban designers, based on Top 100 configurations (out of 1600), for improved energy performance and better ventilation of buildings in urban areas.