Objective To investigate the clinical value of hemoperfusion with the neutral macroporous adsorption resin cartridge HA380 in patients with sepsis, and to analyze its effects on inflammatory levels, organ function, and short‑term prognosis. Methods  Eighty patients with sepsis admitted to FAW General Hospital of Jilin Province from January 2024 to December 2025 were enrolled and randomly divided equally into a control group and an observation group. The control group received standard comprehensive treatment for sepsis, while the observation group received additional HA380 hemoperfusion. Inflammatory markers, organ function indicators, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and 28‑day mortality were compared between the two groups before and after treatment to evaluate the therapeutic efficacy. Results After the treatment course, the observation group showed significantly lower levels of C‑reactive protein, procalcitonin, interleukin‑6, tumor necrosis factor‑α, creatinine, and total bilirubin than the control group (Z/t=2.933, ‑2.012, ‑2.926, ‑2.276, 3.222, 2.998; P=0.004, 0.044, 0.003, 0.023, 0.002, 0.004, respectively), and a significantly higher oxygenation index (Z/t=‑4.478, P<0.001). The observation group also had lower SOFA and APACHE II scores than the control group (Z/t=4.418, 4.431, both P<0.001). Survival curve analysis showed that the mortality rate in the control group was higher than that in the observation group (χ²=3.971, P=0.046). Conclusion  HA380 hemoperfusion can effectively remove inflammatory mediators in septic patients, improve organ function, reduce the risk of organ failure and short‑term mortality, and optimize clinical prognosis.