Duckweed species, particularly Lemna minor, are widely found in freshwaters all over the world. This macrophyte provides multiple ecosystems’ functions and services, but its excessive proliferation can have negative environmental impacts (including ecological and socio-economic impacts). This work explores the use of remote sensing tools for mapping the dynamics of Lemna minor in open watercourses, which could contribute to identifying suitable monitoring programs and integrated management practices. The study focuses on a selected section of the Lis River (Portugal), a small river that is often affected by water pollution. The study approach uses spatiotemporal multispectral data from the Sentinel-2 satellite and from 2021 and investigates the potential of remote sensing-based vegetation and water indices (Normalized Difference Vegetation Index (NDVI), Green Normalized Difference Vegetation Index (GNDVI), Normalized Difference Aquatic Vegetation Index (NDAVI), Green Red Vegetation Index (GRVI), Normalized Difference Water Index (NDWI)) for detecting duckweeds’ infestation and its severity. The NDAVI was identified as the vegetation index (VI) that better depicted the presence of duckweeds in the surface of the water course; however, results obtained for the other VIs are also encouraging, with NDVI showing a response that is very similar to NDAVI. Results are promising regarding the ability of remote sensing products to provide insight into the behavior of Lemna minor and to identify problematic sections along small watercourses.