The Isimangaliso Wetland (IW) in KwaZulu-Natal Province of South Africa has a variety of wetlands that contribute valuable ecosystem services to a notable number of people, the natural species habitat, and tourism interests. Wetlands are epoch-making reproducing and nourishing zones for wildlife and give shelters and protection for sea creatures. As with any natural habitat, wetlands are important in supporting species diversity as well as providing the climate moderating element. This study aimed at appraising the spatial pattern of the Isimangaliso Wetland, the potential determinants and effects of the wetland depletion between 1987 and 2017 using remote sensing and GIS approach. Landsat Thematic Mapper (TM) images acquired for 1987, 1997, 2007 and Landsat 8 Thermal Infrared Sensor (TIRS) and  Operational Land Imager (OLI) imagery for 2017 was acquired from the archives of the United States Geological Survey (USGS) for the analysis using ArcGIS 10.2. The Normalized Difference Water Index (NDWI) analyses between 1987 and 2017 successfully revealed the significant depletion of the water surrounding the IW area which might be as a result of natural or human activities which may include climate change, built-up areas, and agricultural activities. In 1987 and 2017, the results showed that wetland extent was 655.416 Km2 and 429.489 Km2 respectively which connotes that IW has witnessed significant changes during the study period over the area. It was also revealed that the other land features (vegetation, built-up, open surface, and rocky surface) over the area increased from 2149.911 Km2 to 2375.838 Km2 in 1987 and 2017 respectively. The overall classification accuracy of 97.55% and Kappa coefficient of 0.941. This wetland depletion might have a significant impact on biodiversity including humans and animals as well as plants thus diminishing its world heritage status. Consequently, this natural gift needs to be conserved to create a livable environment for wetland animals to moderate local climate as well as preserve human wellness and protection by reducing flood disasters and maintaining efficient water quantity and quality in the area.