This research intends to offer a scientific foundation for environmental monitoring and early warning which will aid in the environmental protection management of Qaroun Lake. Qaroun Lake is increasingly influenced by untreated wastewater discharge from many anthropogenic activities, making it vulnerable to pollution. For that, six environmental pollution indices, namely contamination factor (Cf), enrichment factor (EF), geo-accumulation index (Igeo), degree of contamination (Dc), pollution load index (PLI), and potential ecological risk index (RI), were utilized to assess the bottom sediment and to determine the different geo-environmental variables affecting the lake system. Cluster analysis (CA), and principal component analysis (PCA) were used to explore the potential pollution sources of heavy metal. Moreover, the efficiency of partial least-square regression (PLSR) and multiple linear regression (MLR) were tested to assess the Dc, PLI, and RI depending on the selected elements. The sediment samples were carefully collected from 16 locations of Qaroun Lake in two investigated years in 2018 and 2019. Total concentrations of Al, As, Ba, Cd, Co, Cr, Cu, Fe, Ga, Hf, Li, Mg, Mn, Mo, Ni, P, Pb, Sb, Se, Zn, and Zr were quantified using inductively coupled plasma mass spectra (ICP-MS). According to the Cf, EF, and Igeo results, As, Cd, Ga, Hf, P, Sb, Se, and Zr demonstrated significant enrichment in sediment and were derived from anthropogenic sources. According to Dc results, all collected samples were categorized under a very high degree of contamination. Further, the results of RI showed that the lake is at very high ecological risk. Meanwhile, the PLI data indicated 59% of lake was polluted and 41% had PLI < 1. The PLSR and MLR models based on studied elements presented the highest efficiency as alternative approaches to assess the Dc, PLI, and RI of sediments. For examples, the validation (Val.) models presented the best performance of these indices, with R2val = 0.948–0.989 and with model accuracy ACCv = 0.984–0.999 for PLSR, and with R2val = 0.760–0.979 and with ACCv = 0.867–0.984 for MLR. Both models for Dc, PLI, and RI showed that there was no clear overfitting or underfitting between measuring, calibrating, and validating datasets. Finally, the combinations of Cf, EF, Igeo, PLI, Dc, RI, CA, PCA, PLSR, and MLR approaches represent valuable and applicable methods for assessing the risk of potentially harmful elemental contamination in the sediment of Qaroun Lake.