Remote sensing datasets offer a unique opportunity to observe spatial and temporal trends in water quality indicators (WQIs), such as chlorophyll-a, salinity, and turbidity, across various aquatic ecosystems. In this study, we used available in situ WQI measurements (chlorophyll-a: 17, salinity: 478, and turbidity: 173) along with Landsat-8 surface reflectance data to examine the capability of empirical and machine learning (ML) models in retrieving these indicators over Matagorda Bay, Texas, between 2014 and 2023. We employed 36 empirical models to retrieve chlorophyll-a (12 models), salinity (2 models), and turbidity (22 models) and 4 ML families—deep neural network (DNN), distributed random forest, gradient boosting machine, and generalized linear model—to retrieve salinity and turbidity. We used the Nash–Sutcliffe efficiency coefficient (NSE), correlation coefficient (r), and normalized root mean square error (NRMSE) to assess the performance of empirical and ML models. The results indicate that (1) the empirical models displayed minimal effectiveness when applied over Matagorda Bay without calibration; (2) once calibrated over Matagorda Bay, the performance of the empirical models experienced significant improvements (chlorophyll-a—NRMSE: 0.91 ± 0.03, r: 0.94 ± 0.04, NSE: 0.89 ± 0.06; salinity—NRMSE: 0.24 ± 0, r: 0.24 ± 0, NSE: 0.06 ± 0; turbidity—NRMSE: 0.15 ± 0.10, r: 0.13 ± 0.09, NSE: 0.03 ± 0.03); (3) ML models outperformed calibrated empirical models when used to retrieve turbidity and salinity, and (4) the DNN family outperformed all other ML families when used to retrieve salinity (NRMSE: 0.87 ± 0.09, r: 0.49 ± 0.09, NSE: 0.23 ± 0.12) and turbidity (NRMSE: 0.63± 0.11, r: 0.79 ± 0.11, NSE: 0.60 ± 0.20). The developed approach provides a reference context, a structured framework, and valuable insights for using empirical and ML models and Landsat-8 data to retrieve WQIs over aquatic ecosystems. The modeled WQI data could be used to expand the footprint of in situ observations and improve current efforts to conserve, enhance, and restore important habitats in aquatic ecosystems.