With increasing global population, innovations in agriculture will be essential for a sustainable food supply. We compare commercial CuO NP to synthesized Cu3(PO4)2·3H2O nanosheets to determine the influence of coordinating anion, particle morphology, and dissolution profile on Fusarium oxysporum f. sp. niveum induced disease in watermelon. Copper dissolution in organic acid solutions that mimic complexing agents found in plants was increased by 2 orders of magnitude relative to water. Cu3(PO4)2·3H2O nanosheets showed a rapid initial dissolution, with equilibration after 24 h; CuO NP exhibited continuous particle dissolution. In a greenhouse study, Cu3(PO4)2·3H2O nanosheets at 10 mg/L significantly repressed fungal disease as measured by yield and by a 58% decrease in disease progress. Conversely, CuO NP only yielded significant effects on disease at 1000 mg/L. In field studies, similar enhanced disease suppression was noted for Cu3(PO4)2·3H2O nanosheets, although biomass and yield effects were variable. The method of application was a significant factor in treatment success, with the dip method being more effective than foliar spray; this is likely due to homogeneity of coverage during treatment. The data show that Cu-based nanoscale materials can be an effective and sustainable strategy in the crop disease management but that particle characteristics such as morphology, coordination environment, and dissolution profile will be important determinants of success.