In recent years, residential buildings designed with high window-to-wall ratios regardless of direction have become widespread. These design solutions cause thermal discomfort, especially overheating, and increased energy consumption and cooling load. The main aim of this study is to determine the most and least sensitive design variables affecting energy consumption and thermal comfort of an existing residential building and to find optimum retrofit solutions reducing energy consumption while improving thermal comfort. The south-facing residential block built in 2019, located in the Mediterranean climate region, was selected as the case. The simulation model created in DesignBuilder was calibrated according to hourly monitored indoor temperature data for eight-months period. Uncertainty and sensitivity analysis was performed due to eliminate the design variables with low sensitivity. NSGA-II algorithm was performed. Six retrofit scenarios were defined: building envelope features as passive ones, HVAC system features as active ones, and all design variables as combination. While the first three scenarios aim to minimize energy consumption and discomfort hours, the other three scenarios aim to minimize cooling load and discomfort hours. In conclusion, cooling-heating set point, shading type, infiltration rate, and window-to-wall ratios were defined high sensitivity variables. The heating system operating schedule, cooling system performance coefficient, heating system efficiency, partition wall type, and window frame type variables have low sensitivity for thermal comfort and energy consumption. Optimum solutions in which both objective functions decreased compared to the base case were found in the third and sixth scenarios. In these scenarios, the overheating problem has been solved by evaluating both active and passive solutions.