The optimal conditioning regimen for high-risk myelodysplastic syndrome (MDS) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains elusive. This study aimed to explore the anti-leukemic efficacy and toxicity of Decitabine (Dec, 20 mg/m2/day, day -11 to -7) intensified BUCY2 vs. traditional regimen in high-risk MDS population. We retrospectively evaluated 93 consecutive high-risk MDS patients undergoing allo-HSCT in our institution, comparing discrepancies in clinical characteristics and outcomes between cases using Dec-intensified BUCY2 (n = 52) and traditional BUCY2 regimen (n = 41). Three-year cumulative incidence of relapse after Dec-intensified BUCY2 conditioning was remarkably lower than that of patients using BUCY2 regimen (20.2% vs. 39.0%, p = 0.034). Overall survival and disease-free survival at 3 years for Dec-intensified BUCY2 group were 70.2% and 64.9%, respectively, which were significantly improved when compared with BUCY2 group (51.1% and 43.9%, p = 0.031 and p = 0.027). Furthermore, overall survival and disease-free survival for MDS cases receiving cytoreduction therapy were dramatically better than patients in non-cytoreduction group (p = 0.041, p = 0.047). In summary, the Dec-intensified conditioning regimen could be effective and feasible, providing prominent recurrence control with moderate toxicity for high-risk MDS patients. These patients might also benefit from pre-transplant cytoreductive therapeutic schedules. Larger randomized controlled trials are still needed to further confirm these conclusions.