This study explored the use of foliar sprays with nanoparticles (NP) of B, CuO, MnO, SiO, TiO, and ZnO to protect watermelon against Fusarium wilt. Leaves of young watermelon plants were sprayed (1 to 2 ml per plant) with NP suspensions (500 to 1,000 µg/ml) and were planted in potting mix infested with Fusarium oxysporum f. sp. niveum. In five of eight greenhouse experiments, CuO NP suppressed disease and, in six of eight experiments, CuO NP increased biomass or yield more than in untreated controls or other tested NP. More root Cu was detected in CuO NP-treated plants than other treatments (P = 0.015). In Griswold, CT, plants treated with CuO NP yielded 39% more fruit than untreated controls. In Hamden, CT, treatment with CuO NP produced 53% more fruit when compared with controls (P = 0.02) and was superior to other Cu fungicides. Gene expression in watermelon roots revealed strong upregulation of polyphenol oxidase (PPO) and PR1 genes when CuO NP and F. oxysporum f. sp. niveum were both present. Enzymatic assays for PPO supported the gene expression results. CuO NP may serve as a highly effective delivery agent for this micronutrient to suppress disease.