Accurate quantification of land use/cover change (LULCC) is important for efficient environmental management, especially in regions that are extremely affected by climate variability and continuous population growth such as West Africa. In this context, accurate LULC classification and statistically sound change area estimates are essential for a better understanding of LULCC processes. This study aimed at comparing mono-temporal and multi-temporal LULC classifications as well as their combination with ancillary data and to determine LULCC across the heterogeneous landscape of southwest Burkina Faso using accurate classification results. Landsat data (1999, 2006 and 2011) and ancillary data served as input features for the random forest classifier algorithm. Five LULC classes were identified: woodland, mixed vegetation, bare surface, water and agricultural area. A reference database was established using different sources including high-resolution images, aerial photo and field data. LULCC and LULC classification accuracies, area and area uncertainty were computed based on the method of adjusted error matrices. The results revealed that multi-temporal classification significantly outperformed those solely based on mono-temporal data in the study area. However, combining mono-temporal imagery and ancillary data for LULC classification had the same accuracy level as multi-temporal classification which is an indication that this combination is an efficient alternative to multi-temporal classification in the study region, where cloud free images are rare. The LULCC map obtained had an overall accuracy of 92%. Natural vegetation loss was estimated to be 17.9% ± 2.5% between 1999 and 2011. The study area experienced an increase in agricultural area and bare surface at the expense of woodland and mixed vegetation, which attests to the ongoing deforestation. These results can serve as means of regional and global land cover products validation, as they provide a new validated data set with uncertainty estimates in heterogeneous ecosystems prone to classification errors.