The total suspended matter (TSM) variability plays a crucial role in a lake’s ecological functioning and its biogeochemical cycle. Sentinel-2A MultiSpectral Instrument (MSI) and Landsat 8 Operational Land Instrument (OLI) data offer unique opportunities for investigating certain in-water constituents (e.g., TSM and chlorophyll-a) owing to their spatial resolution (10–60 m). In this framework, we assessed the potential of MSI–OLI combined data in characterizing the multi-temporal (2014–2018) TSM variability in Pertusillo Lake (Basilicata region, Southern Italy). We developed and validated a customized MSI-based TSM model (R2 = 0.81) by exploiting ground measurements acquired during specific measurement campaigns. The model was then exported as OLI data through an intercalibration procedure (R2 = 0.87), allowing for the generation of a TSM multi-temporal MSI–OLI merged dataset. The analysis of the derived multi-year TSM monthly maps showed the influence of hydrological factors on the TSM seasonal dynamics over two sub-regions of the lake, the west and east areas. The western side is more influenced by inflowing rivers and water level fluctuations, the effects of which tend to longitudinally decrease, leading to less sediment within the eastern sub-area. The achieved results can be exploited by regional authorities for better management of inland water quality and monitoring systems.