The accuracy of determining arsenic and lead using the optical technique Slurry–Total Reflection X-ray Fluorescence (Slurry-TXRF) was significantly enhanced through the application of a machine learning method, aimed at improving the ecological risk assessment of agricultural soils. The overlapping of the arsenic Kα signal at 10.55 keV with the lead Lα signal at 10.54 keV due to the relatively low resolution of TXRF could compromise the determination of lead. However, by applying a Partial Least Squares (PLS) machine learning algorithm, we mitigated interference variations, resulting in improved selectivity and accuracy. Specifically, the average percentage error was reduced from 15.6% to 9.4% for arsenic (RMSEP improved from 5.6 mg kg−1 to 3.3 mg kg−1) and from 18.9% to 6.8% for lead (RMSEP improved from 12.3 mg kg−1 to 5.03 mg kg−1) compared to the previous univariable model. This enhanced predictive accuracy, within the set of samples concentration range, is attributable to the efficiency of the multivariate calibration first-order advantage in quantifying the presence of interferents. The evaluation of X-ray fluorescence emission signals for 26 different synthetic calibration mixtures confirmed these improvements, overcoming spectral interferences. Additionally, the application of these models enabled the quantification of arsenic and lead in soils from a viticultural subregion of Chile, facilitating the estimation of ecological risk indices in a fast and reliable manner. The results indicate that the contamination level of these soils with arsenic and lead ranges from moderate to considerable.