The availability of Landsat data allows improving the monitoring and assessment of large-scale areas with land cover changes in rapid developing regions. Thus, we pretend to show a combined methodology to assess land cover changes (LCCs) in the Hamoun Wetland region (Iran) over a period of 30-year (1987–2016) and to quantify seasonal and decadal landscape and land use variabilities. Using the pixel-based change detection (PBCD) and the post-classification comparison (PCC), four land cover classes were compared among spring, summer, and fall seasons. Our findings showed for the water class a higher correlation between spring and summer (R² = 0.94) than fall and spring (R² = 0.58) seasons. Before 2000, ~ 50% of the total area was covered by bare soil and 40% by water. However, after 2000, more than 70% of wetland was transformed into bare soils. The results of the long-term monitoring period showed that fall season was the most representative time to show the inter-annual variability of LCCs monitoring and the least affected by seasonal-scale climatic variations. In the Hamoun Wetland region, land cover was highly controlled by changes in surface water, which in turn responded to both climatic and anthropogenic impacts. We were able to divide the water budget monitoring into three different ecological regimes: (1) a period of high water level, which sustained healthy extensive plant life, and approximately 40% of the total surface water was retained until the end of the hydrological year; (2) a period of drought during high evaporation rates was observed, and a mean wetland surface of about 85% was characterized by bare land; and (3) a recovery period in which water levels were overall rising, but they are not maintained from year to year. After a spring flood, in 2006 and 2013, grassland reached the highest extensions, covering till more than 20% of the region, and the dynamics of the ecosystem were affected by the differences in moisture. The Hamoun wetland region served as an important example and demonstration of the feedbacks between land cover and land uses, particularly as pertaining to water resources available to a rapidly expanding population.