The increased use of copper oxide nanoparticles (CuO NPs) in commercial products and industrial applications raises concerns about their adverse effects on aquatic life and human health. Therefore, the current study explored the removal of CuO NPs from water via coagulation by measuring solubility under various pH values and humic acid (HA) concentrations. The results showed that the media pH significantly affected the coagulation efficiency of CuO NPs (30 mg/L) under various (0–0.30 mM) ferric chloride (FC) dosages. The concentration of dissolved Cu2+ ions at pH 3–6 was (16.5–4.8 mg/L), which was higher than at other studied pH (7–11). Moreover, the simultaneous effect of coagulants and charge neutralization at pH 6–8 enhanced the removal of CuO NPs. At a lower FC (0–0.05 mM) dosage, the higher HA concentration inhibited the aggregation of CuO NPs. However, at the optimum dose of (0.2 mM) FC, the efficiency of turbidity removal and solubility of CuO NPs between pH 8 and 11 was above 98% and 5%, respectively, probably due to coagulant enmeshment. Our study suggested that coagulation was effective in removing the CuO NPs from the complex matrices with pH values ranging from 8–11. The findings of the present study provide insight into the coagulation and dissolution behavior of CuO NPs during the water treatment process.