Powdery mildew disease of peppers (Capsicum annuum L.) caused by Oidiopsis sicula is the most damaging disease in the field and greenhouse. Chemical control has been widely used for the control of powdery mildew. To minimize the deleterious impacts of fungicides, the present study aimed to evaluate the antifungal effect of different concentrations (100, 150 and 200 mg/L) of MgONPs and ZnONPs against powdery mildew in comparison with the conventional fungicide penconazole (0.25 ml/L) under greenhouse conditions. The synthesis and characterization of MgO and ZnONPs were carried out. Dynamic light scattering (DLS) analysis revealed the presence of MgONPs and ZnONPs at the nanoscale level with a size average of 52.97 nm ± 1.43 S.D and 79.45 nm ± 1.74 S.D, respectively. Two foliar sprays were applied at two-week intervals on pepper plants cv. Dolma, naturally infected with powdery mildew in the three greenhouses of El -Dokki (GH-1), Toukh (GH-2) and El-Haram (GH-3). Both MgONPs and ZnONPs markedly reduced disease severity (DS) and area under the disease progress curve (AUDPC) at a concentration of 200 mg/L. Statistical analysis showed a significant (p < 0.05) difference between treatments in the three greenhouses as well as between means of combined treatments. Scanning electron micrographs confirmed that MgONPs and ZnONPs caused inhibition and alterations in the treated fungal structures. Pepper plants treated with penconazole displayed the highest peroxidase activity and recorded 1.229 ΔA422/10 sec/g FW. While, the highest polypheneloxidase activitiy was obtained by MgONPs with value reached 0.283 ΔA495/10 sec/g FW . Out of all treatments, MgONPs were the superior in increasing total chlorophyll at the three applied concentrations, with values of 74.81, 82.94, and 91.19 mg/g^-1 FW, respectively. Cytotoxic investigations exhibited the clastogenic nature of MgONPs, ZnONPs, and penconazole. The obtained results are encouraging and emphasize the recognition of MgONPs and ZnONPs as a viable alternatives to conventional strategies.