Long-distance trade routes have played a fundamental role in shaping and transforming the spatial organization of Iranian cities throughout history. These routes not only facilitated the movement of goods, people, and information but also determined the functional hierarchy of cities at both regional and interregional scales. However, the interrelation between trade networks and the spatial organization of inland cities has rarely been examined in a systematic manner. This study aims to reinterpret the role of trade routes in the spatial organization of Iranian inland cities through an analytical investigation of Hamedan’s position within Iran’s communication network from the Safavid to the late Qajar period. The research adopts a qualitative–historical approach, utilizing data derived from historical maps, travelogues, consular reports, and descriptive documents, analyzed through comparative and interpretive methods. The analytical framework integrates three interdisciplinary perspectives: the concept of the “gateway city” in economic geography, the “transaction cost” theory in spatial economics, and the notion of “path dependence” in urban historical studies. Findings reveal that since the medieval period, Hamedan has functioned as an active intermediary node along the east–west and north–south trade corridors, benefiting from an intermediate positional advantage within domestic and transregional exchange networks. With the global shift of trade routes, the expansion of maritime transportation, and geopolitical instability in western borders, this position gradually weakened, and the city transitioned from a linear and centralized structure to a multi-centered and regionally oriented pattern. These transformations were reflected in the city’s morphological development, the decline of market centrality, and the increasing autonomy of local neighborhoods. The study concludes that historical Iranian cities, including Hamedan, should be understood as dynamic nodes within broader trade networks, whose spatial vitality and morphological continuity have been directly shaped by the persistence or disruption of these networks.