The present study investigated the effects of foliar application of zinc (Zn) and selenium (Se) on bioavailability of Zn and Se and toxicity of cadmium (Cd) and lead (Pb) to different water spinach ecotypes (LA and HA) grown in slightly (XZ) or moderately (LJY) contaminated fields via in vitro digestion combined with Caco-2/HL-7702 cell model. The obtained results revealed that foliar application of Zn and Se promoted yield, increased total, bioaccessible and bioavailable fractions of Zn and Se in plants, indicating that foliar application is a feasible way of biofortification. Although there was no significant effect on liver cell proliferation (MTT), membrane stability (LDH) and hepatocyte enzyme (ALT and AST) activities, the obvious ecotype and soil dependent fluctuations of lipid peroxidation (MDA) and antioxidant enzyme (SOD, POD and CAT) activities in serum highly suggest that the low accumulator and clean field should be used in agricultural production rather than the high accumulator and contaminated farmland. Moreover, foliar application of Zn and Se improved nutritional quality of all water spinach genotypes in both fields, including increased Fe, vitamin C, cellulose and chlorophyll, maintained concentrations of potassium (K), manganese (Mn), copper (Cu), protein, and nitrate. These results demonstrate that this agricultural management practice may prove to be an effective approach for minimizing health risk and alleviating “hidden hunger” in the developing countries.