ABSTRACT Plant viruses are so harmful to crops. It is an urgent need to develop modern, environment‐friendly, and sustainable plant viral epidemic‐management strategies that are safe for both human health and the environment. The field of nanotechnology is gaining increased interest in plant science. Magnesium oxide nanoparticles (MgONPs) have typical physical and chemical characteristics of nanomaterials. Hence, in this study, we systematically investigated the molecular mechanism of MgONPs triggering the plant immunity against viral pathogens. Foliar treatments allow MgONPs to enter Nicotiana benthamiana leaves through stomata and distribute within the intracellular space around chloroplasts through penetrating cell walls. MgONPs elevate plant growth and trigger dose‐dependent plant immunity against viral pathogens. Application of MgONPs triggers glutamate‐like receptors‐dependent Ca 2+ flux and Ca 2+ sensors. Exogenous application of MgONPs does not trigger resistance in Ca 2+ channel‐blocked plants, and knockout of NbGLR3.3 weakens the resistance induced by MgONPs. MgONPs induce early ROS bursts but reduce oxidative damage and accumulation of ROS after TMV infection at late stages. MgONPs activate Ca 2+ ‐dependent SA‐, JA‐, and ET‐mediated signalling pathways, and the absence of SA‐, JA‐, or ET signals weakens the MgONPs‐triggered resistance. However, MgONPs fail to induce resistance to viral pathogens in plants simultaneously lacking SA, JA, and ET. Safety evaluation showed that MgONPs have desirable biocompatibility and biosafety for plants, as well as satisfactory biosafety for the aquatic environment. Overall, our discoveries point to a new direction for MgONPs as effective, non‐drug‐resistant, non‐toxic, sustainable, residual‐free, and eco‐friendly antiviral agents to simultaneously prevent diverse viral diseases.