Early blight is a disease that greatly affects Solanaceae, mainly damaging tomato plants, and causing significant economic losses. Although there are methods of biological control, these are very expensive and often their mode of action is slow. Due to this, there is a need to use new techniques that allow a more efficient control of pathogens. Nanotechnology is a new alternative to solve these problems, allowing the creation of new tools for the treatment of diseases in plants, as well as the control of pathogens. The aim of the present investigation was to evaluate the foliar application of selenium and copper in the form of nanoparticles in a tomato crop infested by Alternaria solani. The severity of Alternaria solani, agronomic variables of the tomato crop, and the changes in the enzymatic and non-enzymatic antioxidant compounds were evaluated. The joint application of Se and Cu nanoparticles decreases the severity of this pathogen in tomato plants. Moreover, high doses generated an induction of the activity of the enzymes superoxide dismutase, ascorbate peroxidase, glutathione peroxidase (GPX) and phenylalanine ammonia lyase in the leaves, and the enzyme GPX in the fruit. Regarding non-enzymatic compounds in the leaves, chlorophyll a, b, and totals were increased, whereas vitamin C, glutathione, phenols, and flavonoids were increased in fruits. The application of nanoparticles generated beneficial effects by increasing the enzymatic and non-enzymatic compounds and decreasing the severity of Alternaria solani in tomato plants.