Viruses pose a serious threat to the sustainable production of economically important crops around the world. In the past 20 years, potato virus Y (PVY) emerged as a relatively new and very serious problem in potatoes, even though it is the oldest known plant virus. Multiple strains of the virus cause various symptoms on the leaves and tubers of potatoes, resulting in yield reduction and poor-quality tubers. Consequently, it would be very interesting to learn what causes systemic PVY resistance in plants. Natural compounds such as chitosan (CHT) and phosphorus have been developed as alternatives to chemical pesticides to manage crop diseases in recent years. In the current study, potato leaves were foliar-sprayed with chitosan and phosphorus to assess their ability to induce PVY resistance. Compared to untreated plants, the findings demonstrated a significant decrease in disease severity and PVY accumulation in plants for which CHT and P were applied. Every treatment includes significantly increased growth parameters, chlorophyll content, photosynthetic characteristics, osmoprotectants (glycine betaine, proline, and soluble sugar), non-enzymatic antioxidants (glutathione, phenols, and ascorbic acid), enzymatic antioxidants (peroxidase, superoxide dismutase, lipoxygenase, glutathione reductase, catalase, β-1,3 glucanase, and ascorbate peroxidase), phytohormones (gibberellic acid, indole acetic acid, jasmonic acid, and salicylic acid), and mineral content (phosphorus, nitrogen, and potassium), compared to infected plants. However, compared to PVY infection values, CHT and P treatments showed a significant decrease in malondialdehyde, DPPH, H2O2, O2, OH, and abscisic acid levels. In addition, increased expression levels of some regulatory defense genes, including superoxide dismutase (SOD), ascorbic acid peroxidase (APX), relative pathogenesis-related 1 basic (PR-1b), and relative phenylalanine ammonia-lyase (PAL), were found in all treated plants, compared to PVY-infected plants. Conclusion: Phosphorus is the most effective treatment for alleviating virus infections.