Monitoring ecological indicators is important for assessing impacts of human activities on ecosystems. A means of identifying and applying appropriate indicators is a prerequisite for: environmental assessment; better assessment and understanding of ecosystem health; elucidation of biogeochemical trends; and more accurate predictions of future responses to global change, particularly those due to anthropogenic disturbance. The challenge is to derive meaningful indicators of change that capture the complexities of ecosystems yet can be monitored consistently over large areas and across time. In this study, methods for monitoring indicators of land cover (LC) and forest change were developed using multi-sensor Landsat imagery. Mapping and updating procedures were applied to the Humber River Basin (HRB) in Newfoundland and Labrador, one of four test sites in Canada selected for testing the development of national-scale methods. Procedures involved unsupervised clustering and labeling of baseline imagery, followed by image-to-image spectral clustering to derive binary change masks within which new LC types were classified for non-baseline imagery. Updated maps were compatible with the baseline map and reflected change in LC for three time periods: 1976–1990, 1990–2001, and 2001–2007. From the LC products, several change indicators were quantified including: forest depletion, forest regeneration, forest change, net forest change, and annual rates of change. The procedures were validated using field plots to assess the accuracy of the 2007 LC product (74.2% for 10 LC classes) and change classes observed from 2001 to 2007 (87.8% for four change classes: depletion, regeneration, non-treed class no change, and treed class no change). Methods were considered to be highly efficient and operationally feasible over large areas spanning multiple Landsat scenes. Specific results for the test site provided trend information supporting land and resource management in the HRB region.