Advancements in remote sensing and computational tools have increased our awareness of large-scale environmental problems, thereby creating a need for monitoring, assessment, and management at these scales. Over the last decade, several watershed and regional multi-metric indices have been developed to assist decision-makers with planning actions of these scales. However, these tools use remote-sensing products that are subject to land-cover misclassification, and these errors are rarely incorporated in the assessment results. Here, we examined the sensitivity of a landscape-scale multi-metric index (MMI) to error from thematic land-cover misclassification and the implications of this uncertainty for resource management decisions. Through a case study, we used a simplified floodplain MMI assessment tool, whose metrics were derived from Landsat thematic maps, to initially provide results that were naive to thematic misclassification error. Using a Monte Carlo simulation model, we then incorporated map misclassification error into our MMI, resulting in four important conclusions: (1) each metric had a different sensitivity to error; (2) within each metric, the bias between the error-naive metric scores and simulated scores that incorporate potential error varied in magnitude and direction depending on the underlying land cover at each assessment site; (3) collectively, when the metrics were combined into a multi-metric index, the effects were attenuated; and (4) the index bias indicated that our naive assessment model may overestimate floodplain condition of sites with limited human impacts and, to a lesser extent, either over- or underestimated floodplain condition of sites with mixed land use.