This study assesses the spatiotemporal development of land use systems and climate variability in Southwestern Ghana over the past five decades using integrated remote sensing techniques and existing literature. We demonstrated the relationship between Normalized Difference Vegetative Index, Normalized Difference Water Index, Normalized Difference Built-up Index, surface temperature and precipitation using geoinformatics and Pearson's correlation coefficient (r). We found change in land use systems in Southwestern Ghana to be immensely driven by economic and socio-political factors. Interestingly, some biophysical factors have somewhat contributed to this change. Findings revealed a drastic decline in forested areas (−334.8 km2 yr−1) and waterbodies (−4.79 km2 yr−1), along with a dramatic increase in built-up (+137.93 km2/yr) and farmlands/shrubs (+131.97 km2/yr). Change in prevailing microclimatic conditions can be associated with land cover change, considering the impact of major drivers observed over the given period. Results showed a very weak positive correlation between vegetation and temperature (r=0.214). Similarly, built-up correlated positively with vegetation (r= 0.165), water-index (r= 0.818; strong correlation or evidence of association) and temperature (r=0.266). In contrast, other used variables correlated negatively with precipitation. The study serves a seminal guide to land use developers and institutors for effective and sustainable use of natural resources.