Precipitation and temperature enact variable influences on vegetation, impacting the type and condition of land cover, as well as the assessment of change over broad landscapes. Separating the influence of vegetative variability independent and discrete land cover change remains a major challenge to landscape change assessments. The heterogeneous Lerma-Chapala-Santiago watershed of central Mexico exemplifies both natural and anthropogenic forces enacting variability and change on the landscape. This study employed a time series of Enhanced Vegetation Index (EVI) composites from the Moderate Resolution Imaging Spectoradiometer (MODIS) for 2001–2007 and per-pixel multiple linear regressions in order to model changes in EVI as a function of precipitation, temperature, and elevation. Over the seven-year period, 59.1% of the variability in EVI was explained by variability in the independent variables, with highest model performance among changing and heterogeneous land cover types, while intact forest cover demonstrated the greatest resistance to changes in temperature and precipitation. Model results were compared to an independent change uncertainty assessment, and selected regional samples of change confusion and natural variability give insight to common problems afflicting land change analyses.