Coastal waters have high ecological and economic relevance and are globally threatened by intense human activities leading to eutrophication. The decameter resolution of Sentinel-2 Multispectral Instrument (S2-MSI) provides an advantage to detect spatially heterogeneous phenomena that are limited in extent, such as harmful cyanobacterial blooms (cyanoHABs). Chlorophyll-a is typically used in remote sensing of blooms; however, it remains to be evaluated in several coastal regions of the world. The Río de la Plata estuary (South America) provides a key case study due to its highly variable concentrations of suspended sediments, and the increasing frequency of cyanoHABs. Here, we evaluate the potential and limitations of S2-MSI indices to retrieve chlorophylla in these optically complex waters, obtaining regional algorithms and comparing them to previously available ones. We propose an approach to follow the evolution of chlorophyll-a thresholds (10 and 24 lg/L) that can contribute to monitoring programs and early warning strategies of cyanoHABs.