Fungal pathogens pose a persistent threat to crop plants, risking global food security. Anthracnose of sorghum caused by Colletotrichum graminicola causes a considerable loss in sorghum production. This study aimed to manage the anthracnose disease in sorghum using green-synthesized TiO2 nanoparticles using pomegranate peel and to assess their impacts on the agroeconomic attributes of sorghum. Synthesized TiO2 nanoparticles showed strong dose-dependent antifungal activity against C. graminicola and significantly reduced mycelial radial growth, comparable to commercial fungicides. Foliar application of TiO2 at concentrations of 150 and 200 ppm reduced the disease index >60% in pot trials. Additionally, the effect of TiO2 NPs on the growth and yield of sorghum plants and the possible mechanism(s) behind the suppression of anthracnose disease were deciphered. TiO2 NPs also improved shoot and root length, biomass accumulation, penile size, number of grains, and grain weight in sorghum plants infected with C. graminicola. Application of TiO2 NPs significantly increased the content of defense-related biochemicals, including total phenolic contents, activities of defense-related enzymes (PO, PPO, and PAL), photosynthetic pigments (total chlorophyll contents and carotenoids), and total protein contents. Collectively, our study verified the potential of green-synthesized titanium dioxide nanoparticles to suppress anthracnose disease by activating a defense system and stimulating growth and yield promotion under pathogen stress.