Introduction: Blood purification is an option for treatment of the source of sepsis when correcting patients’ septic shock-induced clinical status. We investigated the efficacy of HA330 hemoperfusion adsorbent application with renal replacement therapy in patients with septic shock and acute kidney injury. Methods: This prospective observational study involved 23 patients diagnosed with sepsis who underwent continuous venovenous hemodiafiltration and HA330 hemoperfusion for 2 h once daily for 3 days. The patients’ demographic data, comorbidities, lengths of intensive care unit and hospital stays, blood cell counts, blood biochemistry values, coagulation values, blood gas values, inflammatory markers, hemodynamic parameters, and inotropic medication use before and after each application of HA330 hemoperfusion were recorded. The effectiveness of HA330 hemoperfusion was evaluated by comparing the parameters on days 0 and 1, 1 and 2, and 2 and 3. Results: The pH increased significantly following the first application of HA330 hemoperfusion ( p = 0.001), the C-reactive protein (CRP) and procalcitonin levels decreased significantly after the second application ( p = 0.002 and 0.018, respectively), and the CRP level decreased significantly following the third application ( p = 0.046). Conclusions: The application of HA330 hemoperfusion 2 h daily for 3 consecutive days improved level of CRP and heart rate, but had no effect on others or on the prognosis.