Research on nanoparticles (NPs) is gaining great attention in modulating abiotic stress tolerance and improving crop productivity. Therefore, this investigation was carried out to evaluate the effects of copper oxide nanoparticles (CuO-NPs) on growth and biochemical characteristics in two maize hybrids (YH-5427 and FH-1046) grown under normal conditions or subjected to saline stress. A pot-culture experiment was carried out in the Botanical Research Area of “the University of Lahore”, Lahore, Pakistan, in a completely randomized design. At two phenological stages, both maize hybrids were irrigated with the same amount of distilled water or NaCl solution (EC = 5 dS m−1) and subjected or not to foliar treatment with a suspension of CuO-NPs. The salt stress significantly reduced the photosynthetic parameters (photosynthetic rate, transpiration, stomatal conductance), while the sodium content in the shoot and root increased. The foliar spray with CuO-NPs improved the growth and photosynthetic attributes, along with the N, P, K, Ca, and Mg content in the roots and shoots. However, the maize hybrid YH-5427 responded better than the other hybrid to the saline stress when sprayed with CuO-NPs. Overall, the findings of the current investigation demonstrated that CuO-NPs can help to reduce the adverse effects of salinity stress on maize plants by improving growth and physio-biochemical attributes.