Potato (Solanum tuberosum) crops have experienced a 22% reduction due to attacks from microbial pathogens and pests. Dry rot disease occurred from risks in El-Minya governorate, Egypt, where potato is the major cultivated crop. Potato cultivar ‘Cara’ samples were collected from the markets of six regions in El-Minya for isolation. They were also tested for the application of biosynthesized zinc oxide nanoparticles (ZnONPs) for disease management. The ability of Exserohilum rostratum to synthesize ZnONPs was documented via UV-visible, X-ray diffraction, Fourier transform infrared spectrum, and transmission and scanning electron microscopy. Spherical shape and crystallite small size (51.0 ± 3.0 nm) were attributed to the created ZnONPs. The ZnONPs were applied in the bio-control of the causative agent (Fusarium nygamai) of dry rot disease and large economic loss of potato cv. ‘Cara’ productivity. The mycosynthesized ZnONPs by E. rostratum at 100 μg/ mL (3 mM) showed antifungal activity against F. nygamai with higher reducing value of mycelium growth diameter 2.0 ± 0.14 cm compared to Revanol 50%, traditional product with a diameter of 3.85 ± 0.10 cm. Overall, ZnONPs are an excellent agent that can be applied to repress the most common fungal disease of potato.