Energy efficiency is a key indicator of sustainability in buildings. The building sector accounts for more than one-third of global energy consumption and carbon emissions. Prefabricated buildings play a crucial role in advancing higher energy efficiency standards, particularly through their performance in production, construction, waste reduction, and overall life cycle impact. Prefabrication is a core component of modular building systems, which have recently gained attention, especially for their applications in residential construction. This paper explores innovative approaches to sustainable architectural design by integrating universal ecological strategies with advanced energy design principles. A novel combinatorial building optimization method, supported by building physics simulations, is introduced to identify optimal building configurations that balance occupant comfort and energy performance. The methodology employs modular spatial units, allowing for diverse mass configurations tailored to single-family housing. These configurations are evaluated through sensitivity analyses focused on roof geometry, glazing ratios, and orientation. Dynamic thermal simulations assess both thermal and visual comfort, alongside energy efficiency performance. The study identifies 99 massing configurations. Results indicate that south-oriented, two-story modular configurations with higher glazing ratios provide optimal thermal and visual comfort while reducing heating demand. However, increased glazing also leads to higher cooling loads. This research contributes to the field by demonstrating a scalable and adaptable design framework that enhances environmental performance while maintaining practical applicability within the residential building sector.