The purpose of the current study was to determine the possible improvement in soybean plants’ tolerance against vanadium-induced stress in response to the application of olive solid waste (OSW) and selenium nanoparticles (Se-NPs), by assessing metabolites and plant defense systems. Drawing upon this aim, a pot experiment was performed where the soybean plants were grown with a fertilization treatment (including, control, OSW, Se-NPs, and Se-NPs + OSW) under vanadium stress (including non-stress and 350 mg sodium orthovanadate per kg of soil). Enhancement of hydrogen peroxide (H2O2) and malondialdehyde (MDA) accumulation in vanadium-stressed plants confirmed the oxidative damage in unfertilized plants. Results indicated the positive effects of the combined treatment (Se-NPs + OSW) in improving the plant stress tolerance by causing a balance in the produced ROS and detoxified ROS in the plant. It was mainly stimulated through the improvement of the photosynthetic parameters, anthocyanin metabolism pathway, phenylpropanoid pathway, non-enzymatic antioxidant metabolites (tocopherols, malondialdehyde, polyphenols, and flavonoids), antioxidant enzymes, and biochemical components involved in the ASC/GSH cycle (ascorbate, ascorbate peroxidase, dehydroascorbate reductase, monodehydroascorbate reductase, glutathione, glutathione reductase, and glutathione peroxidase), and antioxidant direct scavenging enzymes (peroxidase, catalase, and superoxide dismutase), which finally resulted in higher plant biomass. In conclusion, the simultaneous application of OSW and Se-NPs treatments provided a reliable protection for soybean plants in vanadium-contaminated soils through the activation of antioxidant and non-antioxidant defense mechanisms.