In this paper, an optimization-based analysis approach is presented to cost-effectively improve the energy efficiency of residential buildings in Morocco. This study introduces a unique focus on the Moroccan context, where a comprehensive application of energy efficiency optimization has not yet been undertaken. This analysis considers the interactive effects among various energy efficiency measures to determine optimal combinations for designing high-energy performance, as well as net-zero energy, residential buildings for six climate zones in Morocco. In particular, the design analysis approach combines a whole-building simulation with the sequential search technique, providing a novel, integrated cost–benefit analysis that minimizes lifecycle costs (LCC) while maximizing energy savings for each climate zone. This study also includes an unprecedented comparison of optimized designs, reference designs, and current Moroccan building regulations (RTCM), highlighting potential improvements to the existing regulatory framework. While the sequential search method has been applied elsewhere, its specific application to achieve net-zero energy homes in the Moroccan context with comparable LCC is a new contribution. The analysis results show that houses in Morocco can be cost-effectively designed to achieve annual energy savings of 51% for Zone 1, 53% for Zone 2, 60% for Zone 3, 67% for Zone 4, 54% for Zone 5, and 56% for Zone 6 compared to the current construction practices considered as reference designs. Moreover, the results indicate that houses can reach net-zero energy building designs with almost the same LCC as the reference design cases for all the climate zones in Morocco.