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About 45% of the world’s fruit and vegetables are wasted, resulting in postharvest losses and contributing to economic losses ranging from $10 billion to $100 billion worldwide. Soft rot disease caused by <i>Rhizopus stolonifer</i> leads to postharvest storage losses of sweet potatoes. Nanoscience stands as a new tool in our arsenal against these mounting challenges that will restrict efforts to achieve and maintain global food security. In this study, three nanomaterials (NMs) namely C₆₀, CuO, and TiO₂ were evaluated for their potential application in the restriction of Rhizopus soft rot disease in two cultivars of sweet potato (Y25, J26). CuO NM exhibited a better antifungal effect than C₆₀ and TiO₂ NMs. The contents of three important hormones, indolepropionic acid (IPA), gibberellic acid 3 (GA-3), and indole-3-acetic acid (IAA) in the infected J26 sweet potato treated with 50 mg/L CuO NM were significantly higher than those of the control by 14.5%, 10.8%, and 24.1%. CuO and C₆₀ NMs promoted antioxidants in both cultivars of sweet potato. Overall, CuO NM at 50 mg/L exhibited the best antifungal properties, followed by TiO₂ NM and C₆₀ NM, and these results were further confirmed through scanning electron microscope (SEM) analysis. The use of CuO NMs as an antifungal agent in the prevention of <i>Rhizopus stolonifer</i> infections in sweet potatoes could greatly reduce postharvest storage and delivery losses.