This article evaluates the effect of depopulation, as a common trend in European countries and post-industrial cities, on the selected components of urban spatial structure, as an example of Łódź (Poland). An integrated land use and transportation model was adapted and calibrated based on the available data in the study area and modeled the evolution of the city structure from 2020 to 2040. For the land use part, the spatial input-output concept and economic base theory are combined to compute the number of activities in the study area. First, the economic sectors (i.e., land, population, base, and service classes) are defined. Second, the production and consumption of each sector in Łódź is calculated. Third, productions and consumptions are allocated to spatial units for determining the level of activities and flow between them. This process, which was programmed in Python, iterates until it reaches equilibrium in the activity system. For the transportation part, the PTV Visum simulator does the tasks of network representation and traffic assignment. Following the existing literature, changes in the distribution of employment, population, and land consumption within the activity system, along with trip length, trip production, and traffic loading in the mobility system, are regarded as urban structure factors and used for assessing the integrated model outputs. Getis-Ord and Theil's indices are also calculated to obtain the auxiliary results. Decentralization and dispersion in the spatial distribution of activities were identified as the chief characteristics of the city form. As the population reduces in Łódź, the average land consumption and service activities per spatial analysis units drop in the simulation period, which lies in the correlation between population decline and the economic fall. In addition, depopulation leads to flattened spatial structure and lesser development intensity due to the scattered and de-intensified pattern of land consumption. Besides, the population shrinkage causes a decrease in inequality level by 60% and 25% from 2020 to 2030 and 2030 to 2040, respectively, which might root in the reduced and lower difference between population and service simultaneously. Moreover, computations showed that while the number of trips decreases, the trip length increases, which means after depopulation, people travel less between spatial units to fulfill their needs because the city shifts to the borderlines. Findings also assist decision- and policy-makers in recognizing the effect of population loss on Łódź’s spatial structure and offer implications of integrated models for addressing such phenomena.