Oxidative stress-induced mitochondrial function and cell apoptosis to osteoblasts, plays a critical role in the pathophysiology of osteoporosis. However, mechanisms underlying such process remain not yet clear. We aims in this study to investigate a possible role of SMAD (the mothers against decapentaplegic homolog 4 (SMAD4) in the oxidative stress-induced apoptosis, in homo sapiens osteoblast hFOB1.19 cells. Results demonstrated that the treatment with more than 100μM H2O2 significantly downregulated the cellular viability, whereas markedly induced apoptosis in hFOB1.19 cells. The SMAD4 was markedly reduced in both mRNA and protein levels in the H2O2 -treated hFOB1.19 cells, along with the reduction of Small ubiquitin-related modifier 1 (SUMO 1) and SUMO 2/3. The immunoprecipitation assay confirmed indicated the interaction between SUMO 1 (or SUMO 2/3) and SMAD4. Moreover, the SMAD4 overexpression markedly ameliorated the H2O2-resulted viability reduction and apoptosis induction in hFOB1.19 cells. Interestingly, such amelioration was blocked by the knockdown of SUMO 2/3. Taken together, we conclued that SMAD4 inhibits the H2O2-induced apoptosis in osteoblast hFOB1.19 cells; such inhibition might depend on the SUMOylation by SUMO 2/3. It implies a promising role of SMAD4 in oxidative stress-promoted damage to osteoblasts.