Depopulation has been a process present in Serbia for decades, with constant progress and spatial expansion. Although depopulation is more common for rural areas, nowadays the population declining is affecting urban areas, as well. This paper is focused on the new possibilities and innovative approaches for detection and monitoring of population dynamics and economic activities, their spatial and temporal patterns and changes in Serbia. Therefore, a set of 12 indicators is created, classified into four groups: demographic indicators, (urban)morphological, (geo)spatial, and composite indicators, based on various datasets. In addition to traditional datasets, which are used to express population quantitative changes, the data relies on alternative sources that were incorporated too, such as satellite images of nighttime lights, digital terrain model, GHS Population Grid datasets, etc. This research is conducted at the municipal level and regarding the deeper insight into studied phenomenon, it has been extended to the settlement level for the territory of Serbia. Data preparation and calculation of indicators were performed in the GIS environment. The chosen approach highlighted the opportunities and advantages of different datasets crossover, which allowed greater precision and applicability of the obtained results and accurate detection of potentially demographically "empty", depopulated areas in Serbia.