Naturally, under field conditions, plants are regularly experienced by a mixture of two or more stress factors. Drought is a major abiotic stress, and fungal pathogens characterize a main biotic stress challenge faced by plants and impact negatively on plant development and productivity. We propose that foliar application of nitric oxide (NO) donors can have positive effects on the induction of tolerance to biotic and abiotic stress on groundnut plants. This investigation was carried out to study the changes in growth, some biochemical aspects, and yield and quality of groundnut plants as well as induction of resistance to Cercospora leaf spot disease in response to nitric oxide (NO) donors, sodium nitroprusside (SNP), and arginine (Arg) (2.5, 5.0, and 7.5 mM) under two water irrigation levels 100% and 75% of water irrigation requirements (WIR), in two field experiments through two successive growing seasons of 2021 and 2022. Decreasing irrigation water significantly reduced shoot length, branches numberplant-1, shoot fresh and dry weight, photosynthetic pigments components, endogenous indole acetic acid (IAA) contents, and yield components. Furthermore, root fresh and dry weight, phenols, total soluble sugars (TSS), proline contents, and the accumulation of hydrogen peroxide (H2O2) and lipid peroxidation of groundnut leaves increased significantly. Contrarily, foliar application with Arg and SNP alleviated the negative influences of drought on growth and productivity of groundnut plants via enhancing photosynthetic pigments, IAA, phenolic compounds, TSS, and proline contents. Additionally, SNP and Arg significantly decreased oxidative damage through decreasing H2O2 and lipid peroxidation by the induction of antioxidant enzymes. Remarkably, the increase of drought level led to a reduction in Cercospora leaf spot (CLS) disease with the use of high concentrations of both Arg and SNP. Interestingly, in both stressed and unstressed plants, SNP treatment at 7.5 mM was the most effective in reducing the incidence and severity of disease, while Arg at 2.5 mM recorded the lowest reduction compared to other treatments. In conclusion, foliar treatment of either SNP or Arg is a profound effect on modulating the drought stress and induction of resistance to Cercospora leaf spot disease of groundnut plants throughout regulating physiological and biochemical processes associated with photosynthesis and oxidative responses.