Understanding drivers of changes in land use/land cover (LULC) is essential for modeling future dynamics or development of management strategies to ameliorate or prevent further decline of natural resources. In this study, an attempt has been made to identify the main drivers behind the LULC changes that had occurred in the past four decades in Munessa-Shashemene landscape of the south-central highlands of Ethiopia. The datasets required for the study were generated through both primary and secondary sources. Combination of techniques, including descriptive statistics, GIS-based processing, and regression analyses were employed for data analyses. Changes triggered by the interplay of more than 12 drivers were identified related to social, economic, environmental, policy/institutional, and technological factors. Specifically, population growth, expansion of cultivated lands and settlements, livestock ranching, cutting of woody species for fuelwood, and charcoal making were the top six important drivers of LULC change as viewed by the local people and confirmed by quantitative analyses. Differences in respondents' perceptions related to environmental (i.e., location specific) and socioeconomic determinants (e.g., age and literacy) about drivers were statically significant (P = 0.001). LULC changes were also determined by distances to major drivers (e.g., the further a pixel is from the road, the less likelihood of changes) as shown by the landscape level analyses. Further studies are suggested targeting these drivers to explore the consequences and future options and formulate intervention strategies for sustainable development in the studied landscape and elsewhere with similar geographic settings.