Complex ecosystems as wetlands are very sensitive to changes and disturbances. Human activities causing habitat fragmentation that alter landscapes affect the wetland ecosystems and negatively influence biodiversity. The health of the ecosystem is measured as a homeostasis between the system components and stability or resilience of the system against disturbance; therefore, any anthropogenic disturbances can cause dramatic changes in the balance of wetland ecosystem. Burullus, the second largest of the Egyptian northern coastal wetlands along the Mediterranean coast, has been recognized recently as critically endangered ecosystem according to an assessment using IUCN Red List of ecosystems. The study sought to assess Burullus wetland’s health based on multispectral indicators related to the structure, function, and resilience of the ecosystem. Three indices were calculated to quantify the health of the wetland: the structure index, vigor index, and resilience index. The overall status of the wetland indicates a dynamic state and rapid transformation, which occurred over the study period. The outcomes indicated that Burullus’s health has progressively deteriorated in the recent investigated years of 2016 and 2019 compared to the reference years of 1984 and 1986. The assessed indicators revealed a trend towards more deterioration of its ecological system due to the LULC transformations, anthropogenic interventions, and overexploitation of its natural resources. In addition, the growth in the impervious surfaces by 9% in the recent years due to expansion in urbanization was detected. All of these factors may affect the ecological balance and the health of the wetland to some extent. The fragility of this wetland and the continuous fragmentation of it occurs due to human activities that threaten its important and unique habitats. The integrated framework for the assessment of Burullus wetland’s health based on remotely sensed data and using geospatial techniques can be utilized for the assessment of other similar coastal wetlands at national and regional scales.