Assessing the environmental hazard of potentially toxic elements in bottom sediments has always been based entirely on ground samples and laboratory tests. This approach is remarkably accurate, but it is slow, expensive, damaging, and spatially constrained, making it unsuitable for monitoring these parameters effectively. The main goal of the present study was to assess the quality of sediment samples collected from Lake Qaroun by using different groups of spectral reflectance indices (SRIs), integrating data-driven (Artificial Neural Networks; ANN) and multivariate analysis such as multiple linear regression (MLR) and partial least square regression (PLSR). Jetty cruises were carried out to collect sediment samples at 22 distinct sites over the entire Lake Qaroun, and subsequently 21 metals were analysed. Potential ecological risk index (RI), organic matter (OM), and pollution load index (PLI) of lake’s bottom sediments were subjected to evaluation. The results demonstrated that PLI showed that roughly 59% of lake sediments are polluted (PLI > 1), especially samples of eastern and southern sides of the lake’s central section, while 41% were unpolluted (PLI < 1), which composed samples of the western and western northern regions. The RI’s findings were that all the examined sediments pose a very high ecological risk (RI > 600). It is obvious that the three band spectral indices are more efficient in quantifying different investigated parameters. The results showed the efficiency of the three tested models to predict OM, PLI, and RI, revealing that the ANN is the best model to predict these parameters. For instance, the determination coefficient values of the ANN model of calibration datasets for predicting OM, PLI, and RI were 0.999, 0.999, and 0.999, while they were 0.960, 0.897, and 0.853, respectively, for the validation dataset. The validation dataset of the PLSR produced R2 values higher than with MLR for predicting PLI and RI. Finally, the study’s main conclusion is that combining ANN, PLSR, and MLR with proximal remote sensing could be a very effective tool for the detection of OM and pollution indices. Based on our findings, we suggest the created models are easy tools for forecasting these measured parameters.