Introduction: Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a major complication following hematopoietic stem cell transplantation, resulting from immune and chemical toxicity in the sinusoidal endothelium and hepatocellular damage. In the most severe cases, multiorgan dysfunction occurs, so it is essential to promptly identify patients at greater risk of SOS/VOD and to adopt prophylactic strategies. Objectives: This study aims to systematize the impact of different approaches as primary prophylaxes against SOS/VOD in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A systematic review and meta-analysis of randomized clinical trials evaluating different strategies for primary prophylaxis of SOS/VOD was carried out in pairwise fashion and with a consistent network structure. The odds ratio (OR) and corresponding confidence intervals were calculated using the random-effects model. Heterogeneity was assessed by the I² method and the efficacy of each approach was estimated by SUCRA (surface under the cumulative ranking curve). Results: Considering all patients undergoing HSCT, ursodeoxycholic acid (UDCA) [OR = 0.38, 95%CI 0.14–1.06, SUCRA = 0.720] was associated with a lower incidence of VOD while defibrotide reached a modest reduction in its incidence [OR = 0.64, 95%CI 0.23–1.67; SUCRA = 0.486]. Considering the subgroup of patients undergoing hematopoietic progenitors allotransplantation, defibrotide scored higher [OR = 0.51, 95%CI 0.09–2.85, SUCRA = 0.650] by comparison with UDCA [OR = 0.53, 95%CI 0.14–1.96, SUCRA = 0.639]. Conclusions: This is the first meta-analysis comparing primary prophylaxes against SOS/VOD. UDCA yielded more promising results when considering all patients undergoing hematopoietic stem cell transplantation, yet, in a subgroup analysis of the ones exposed to allogeneic grafts, it becomes not significantly overrun by defibrotide.