Background <p>Patients with severe acute pancreatitis (SAP) often experience systemic inflammatory responses and microcirculatory disturbances, for which existing treatments have limited intervention effects.</p> Objectives <p>It aimed to investigate the impact of early blood purification on serum inflammatory mediators, hemorheological parameters, and clinical prognosis in patients with SAP.</p> Methods <p>120 patients with SAP were randomly grouped: observation group (OG) (routine treatment + early continuous veno-venous hemodiafiltration) and control group (CG) (routine treatment). The time to clinical symptom improvement, hemorheological parameters [whole blood viscosity (WBV), plasma viscosity (PV), hematocrit, and platelet adhesion rate], and inflammatory mediators were compared. Multivariate logistic regression analysis (MLRA) was used to identify prognostic factors.</p> Results <p>The OG had markedly shorter times to symptom relief for fever, abdominal pain, and abdominal distension (all <i>P &lt;</i> 0.001) and a higher cure rate (<i>P =</i> 0.012); The levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), as well as WBV and PV, were more markedly improved (all <i>P &lt;</i> 0.01). Multivariate analysis suggested that peak CRP (OR = 1.01, <i>P &lt;</i> 0.001) and peak TNF-α (OR = 1.02, <i>P =</i> 0.003) maintained independent predictive value, and all hemorheological parameters were confirmed as independent prognostic factors.</p> Conclusion <p>Early blood purification can effectively improve the inflammatory response and hemodynamics in patients with SAP, with its efficacy influenced by multiple factors, including disease severity, intensity of inflammatory response, and hemorheological status.</p> Clinical trial number <p>Not applicable.</p>