Gray blight caused by Pseudopestalotiopsis sp., is a major foliar disease that significantly reduces both yield and quality of tea [Camellia sinensis (L.) Kuntze]. Although the combined application of selenium (Se) and melatonin (MT) has been shown to effectively mitigate this disease, the underlying mechanisms by which the resistance is enhanced in tea plants remain poorly understood. In the present study, we investigated the inhibitory effects of Se and MT on Ps. camelliae-sinensis and its role in enhancing disease resistance of ‘Shuchazao’ tea plant. The results showed that Se significantly inhibited mycelial growth, with an EC₅₀ of 5.80 μg·mL⁻¹, while MT alone had no significant effect. However, the combination of Se and MT (5.8 mg·L⁻¹ + 200 μmol·L⁻¹) exerted a stronger inhibitory effect on the fungal growth. In vivo experiments demonstrated that Se and MT reduced the lesion diameter by 66.84% and decreased disease severity by 75.8% in tea plants. Transcriptomic and metabolomic analyses revealed that Se and MT regulated secondary metabolite biosynthesis, particularly that of triterpenoids and flavonoids, which are critical for disease resistance. Specifically, Se and MT treatment reduced the accumulation of ten adhesion-related triterpenoids and significantly increased the production of the antifungal compounds Tangeretin and Cinchonain Ib*. These findings suggest the synergistic effects of Se and MT in controlling tea gray blight through direct pathogen inhibition and the induction of defense systems in the host plant via the regulation of higher bioactive compounds and signaling pathways. The combined application of Se and MT offers a promising alternative to chemical fungicides for managing gray blight disease of tea, while also enabling MT-biofortified and/or Se-enriched green tea.