This approach aimed to address the efficacy of the newly synthesized hybrid steroids modified by sulfurheterogenous rings and loaded on mesoporous silica nanoparticles in manipulating metabolic syndrome induced by high fructose diet. The designed compounds were synthesized by mechanochemical process and then loaded on mesoporous silica nanoparticles as drug delivery vehicles. Thereafter, these compounds were examined for counteracting metabolic syndrome inmice. The synthesized compounds revealed potentiality to prevent body weight gain as indicated by the decreased BMI of the mice fed high fructose diet. The hypolipidemic effect of the designed compounds was evidenced by the reduction of serum cholesterol, triglycerides, LDL-cholesterol and the enhancement of HDL-cholesterol levels. Moreover, the compounds displayed a significant decline in blood glucose and insulin levels. So, they exhibited significant betterment in insulin resistance of the treated mice. Furthermore, the treatment with these compounds improved serum spexin level in metabolic syndrome-challenged mice. Ultimately, the tested compounds demonstrated powerful free radical scavenging activity manifested by lowering MDA, NO and H2O2 serum levels. Conclusively, the newly modified hybrid steroid compounds proved good performance against metabolic syndrome in mice most probably due to their content of sulfur atom, in addition to their loading on mesoporous silica nanoparticles.