The effects of nanoparticles (NPs) on plants are contrasting; these depend on the model plant, the synthesis of the nanoparticles (concentration, size, shape), and the forms of application (foliar, substrate, seeds). For this reason, the objective of this study was to report the impact of different concentrations of selenium (Se) and copper (Cu) NPs on yield, antioxidant capacity, and quality of tomato fruit. The different concentrations of Se and Cu NPs were applied to the substrate every 15 days (five applications). The yield was determined until day 102 after the transplant. Non-enzymatic and enzymatic antioxidant compounds were determined in the leaves and fruits as well as the fruit quality at harvest. The results indicate that tomato yield was increased by up to 21% with 10 mg L−1 of Se NPs. In leaves, Se and Cu NPs increased the content of chlorophyll, vitamin C, glutathione, 2,2′-azino-bis(3-ethylbenzthiazolin-6-sulfonic acid (ABTS), superoxide dismutase (SOD), glutathione peroxidase (GPX) and phenylalanine ammonia liasa (PAL). In fruits, they increased vitamin C, glutathione, flavonoids, firmness, total soluble solids, and titratable acidity. The combination of Se and Cu NPs at optimal concentrations could be a good alternative to improve tomato yield and quality, but more studies are needed to elucidate their effects more clearly.