This study aimed to evaluate the prognostic significance of the levels of admission hematocrit (HCT) and the changes in the initial blood urea nitrogen (BUN) levels in predicting the efficacy of blood purification (BP) therapy in ameliorating severe acute pancreatitis (SAP) patients at admission. A retrospective study was conducted on 139 SAP patients from the People's Hospital of Guangxi Zhuang Autonomous Region from 2013 to 2022 and the data retrieved from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database for 346 SAP patients. The patients were stratified based on their HCT0 levels at admission; HCT < 44% (n = 93) and HCT ≥ 44% (n = 46) and ΔBUN levels within the first 24 h post-admission; ΔBUN ≤ 0 (n = 78) and ΔBUN > 0 (n = 61). Propensity score matching (PSM) was performed on factors such as age and gender to control for differences among the strata. The clinical outcomes of the patients receiving or not receiving BP therapy were compared based on the mentioned criteria. Patients with HCT0 ≥ 44%, who were treated with BP showed no significant difference in the 28-day mortality. However, a significant increase in hospital expenses and prolonged ICU stays was observed (P < 0.05). Conversely, patients with ΔBUN ≤ 0 who received BP therapy demonstrated relatively high 28-day mortality rates, prolonged ICU stays, increased hospital expenses, and low SOFA scores (P < 0.05). The analyses of MIMIC-IV database data corroborated these findings. The predictive efficacy of BP therapy in SAP patients was significantly influenced by the changes in BUN levels at 24 h post-admission compared to the initial levels of HCT on admission. Selecting SAP patients suitable for BP treatment should be based on the changes in BUN levels to enhance effective therapeutic outcomes.