The examination of the evolution of domes and their decorations during the Timurid and Safavid periods, both renowned for the grandeur of Iranian architecture, was the main motivation to conduct this research. The present study aimed to examine the comparative effects of internal and external factors, such as changes in religion, governance, cultural transformations, and similar differences, on the design of motifs and construction methods in these periods. The data collection method for this fundamental research was based on documentary studies and library resources, and the nature of the findings analysis was historical and descriptive. It is noteworthy that for selecting the statistical population and study samples, the Bibi Khanum Mosque (Timurid period) and the Chaharbagh School in Isfahan (Safavid period) were considered. The most significant findings and results of this research indicated that the evolution of dome motifs and decorations from the Timurid to the Safavid periods experienced substantial quantitative and qualitative growth. The transition in the techniques of dome covering from mosaic tiles to seven-color tiles, despite the decline in quality, facilitated faster work progress, enabled the execution of detailed Islamic motifs, and provided greater color variety for artists of the Safavid period. Meanwhile, the spiritual and aesthetic functions of domes served as a foundation for spiritual journey and mystical expression for the architects, artists, and patrons (rulers and kings) of both periods.