Mosques are unique in terms of architectural design and operational efficiency. Architectural Design, building envelope characteristics, intermittent operating schedules, and occupancy patterns all impact the performance. Managing these factors poses challenges regarding reducing energy consumption and simultaneously achieving the occupants' thermal and visual comfort, especially in hot, arid climatic conditions. Also, the potential benefits of daylighting in reducing energy consumption in mosque buildings need to be addressed. Accordingly, this study evaluates the impact of various retrofit strategies on the operational performance of Al-Imam Al-Hussein Mosque, one of the large historic mosques in Cairo, considering the energy performance, thermal comfort, and daylighting performance. The current performance of the mosque has been analyzed using energy simulation software to determine the areas that affect its performance. Hence, five retrofitting strategies have been studied to assess their impact on improving the performance of the mosque. When changes are applied to the building envelope only by changing the glazing type, the visual discomfort is improved while sufficient daylighting is maintained inside the prayer area. By adding a cooling system and applying changes to the building envelope, thermal comfort was improved, and the visual discomfort decreased. However, this has led to an increase in energy consumption. Combining different strategies (as in strategy 5) by changing the glazing type, changing the operation scheme, adding LED lamps with dimmers, and adding a cooling system has improved the defined performance metrics. It has achieved a 23% decrease in the annual energy consumption, decreasing the visual discomfort by 30% while maintaining sufficient daylighting conditions inside the space, and enhancing occupants’ thermal comfort by 65%. The proposed approach aids in evaluating the retrofit strategies of mosque buildings, considering different criteria, including daylighting performance, to be energy efficient, sustainable, and maintain occupants’ visual and thermal comfort.