ABSTRACT Climate change has become a severe threat all around the world. Pakistan is also affected by climate change. It has become a severe problem in any part of the country. It is land degradation caused by climatic disturbance and anthropogenic activities. In this study, we used Landsat TM for the years 1980 and 1990, Landsat ETM+ for the years 2000 and 2010, and Landsat OLI/TIRS for the year 2020 were classified using the Maximum Likelihood Classification (MLC) into a built-up area, barren land, vegetation, and water area. This study has been conducted to assess the spatio-temporal analysis of Land Use/Land Cover (LULC) with driving factors from 1980–2020 in the Cholistan Desert, Punjab, Pakistan, and the relationship between different normalized satellite indices with LULC. Post-classification change detection methods were then used to assess the variation over the study period. The built-up area has increased by 6.25% from 1980–2020. The Kappa coefficient was estimated at 0.83, 0.82, 0.83, 0.85, and 0.88 in 1980, 1990, 2000, 2010, and 2020, respectively. At the annual scale (the years 2000 and 2020), a significant positive relationship was observed among LULC, NDVI, and MNDWI for the regions located in the western part of the Cholistan region, while negative trends in the year 1980 to the 2010 year.