Copper oxide nanoparticles (NCuO) have emerged as an alternative to pesticides due to their antifungal effect against various phytopathogens. Combining them with fungicides represents an advantageous strategy for reducing the necessary amount of both agents to inhibit fungal growth, simultaneously reducing their environmental release. This study aimed to evaluate the antifungal activity of NCuO combined with three fungicide models separately: Iprodione (IPR), Tebuconazole (TEB), and Pyrimethanil (PYR) against two phytopathogenic fungi: Botrytis cinerea and Fusarium oxysporum. The fractional inhibitory concentration (FIC) was calculated as a synergism indicator (FIC <= 0.5). The NCuO interacted synergistically with TEB against both fungi and with IPR only against B. cinerea. The interaction with PYR was additive against both fungi (FIC > 0.5). The B. cinerea biomass was inhibited by 80.9% and 93% using 20 mg L-1 NCuO + 1.56 mg L-1 TEB, and 40 mg L-1 NCuO + 12 mu g L-1 IPR, respectively, without significant differences compared to the inhibition provoked by 160 mg L-1 NCuO. Additionally, the protein leakage and nucleic acid release were also evaluated as mechanisms associated with the synergistic effect. The results obtained in this study revealed that combining nanoparticles with fungicides can be an adequate strategy to significantly reduce the release of metals and agrochemicals into the environment after being used as antifungals.