Desertification is one of the major environmental challenges facing sustainable development in arid, semi-arid and subhumid regions. Environmental and anthropogenic qualities are significant indicators to measure the sensitivity of land to desertification. The objective of this study is to evaluate the desertification sensitivity in East Siwa oasis (1763 ha), Egypt, based on the modified MEDALUS approach, using remote sensing and GIS. The application of MEDALUS was based on environmental and anthropogenic qualities such as soil, vegetation, climate, management and water qualities, where five quality indices were calculated based on 22 desertification indicators. Finally, an integrated index was calculated to evaluate the desertification sensitivity. The field data were collected from 73 locations, while the remote sensing data were extracted from Landsat image acquired in 2017. The results revealed that about half of the study area has low quality soils (50.3%) with respect to desertification risks followed by moderate quality soils (49.7%), due to high soil salinity and alkalinity levels. The majority of the study area is characterized by moderate climate quality (72.7%). This is mainly attributed to the scarcity precipitation occurring in the region. The vegetation quality exists in the area is characterized as high (57%) and moderate quality (43%). The areas of high management quality were very limited, representing 14.3% of the study area and the remaining area (85.7%) was under the moderate management quality. The entire study area is characterized by low water quality due to the high salinity levels of irrigation water. It was found that the entire study area is under the critical level of desertification sensitivity, which mainly resulted from natural and human factors. In light of the high desertification risk in the study area, action measures are very necessary to combat desertification and for the sustainable agricultural development.