Objective To explore the therapeutic effect and potential mechanism of CA330 and OXIRIS adsorbent columns in septic shock. Methods Patients who met the diagnostic criteria for septic shock and admitted to the Department of Critical Care Medicine of Shenzhen Third People’s Hospital from February 2022 to June 2024 were selected. They were randomly divided into an OXIRIS group and a CA330 group according to the random number table method. The CA330 group received hemoperfusion combined with hemodiafiltration using CA330 adsorbent co-lumn, while the OXIRIS group was treated with OXIRIS adsorbent column. Relevant markers of the two groups of patients before and after treatment were collected and compared, including inflammatory markers, bilirubin (total bilirubin ［TBil］, direct bilirubin ［DBil］), coagulation functions (prothrombin time ［PT］, activated partial thromboplastin time ［APTT］, etc), endotoxin (ETX), organ function scores (acute physiology and chronic health score Ⅱ ［APACHE Ⅱ］, sequential organ failure assessment ［SOFA］, etc). Molecular biology techniques were adopted to detect changes in inflammation-related gene expression (nuclear factor kappa B ［NF-κB］, toll-like receptor 4 ［TLR4］, myeloid differentiation factor 88 ［MyD88］), and oxidative stress factors (glutathione peroxidase ［GSH-Px］, superoxide dismutase ［SOD］) in the blood of patients before and after treatment. The safety and effectiveness of two types of adsorbent columns during the treatment process was evaluated. Results A total of 92 patients were included and randomly divided into the OXIRIS group and the CA330 group, with 46 cases in each group. After treatment, the levels of TBil, DBil, and ETX in two groups of patients all showed significant decreases compared with before treatment (all P<0.01), the levels of TBil, DBil, and ETX in patients in the OXIRIS group after treatment were all lower than those in the CA330 group during the same period (all P<0.05); PT and APTT in both groups shortened significantly compared with before treatment (both P<0.01), PT and APTT in the OXIRIS group after treatment were both shorter than those in the CA330 group during the same period (both P<0.05); The APACHE Ⅱ score and SOFA score in patients in the OXIRIS group after treatment were both lower than those in the CA330 group during the same period (both P<0.05); The levels of serum high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-5, and IL-8 in patients in both groups showed significant decreases compared with before treatment (all P<0.05), and the levels of these serum markers in the CA330 group after treatment were all lower than those in the OXIRIS group during the same period (all P<0.05). The gene expression levels of NF-κB, TLR4, and MyD88 in patients in the CA330 group after treatment were all lower than those in the OXIRIS group during the same period (all P<0.05); The levels of GSH-Px and SOD in patients in the OXIRIS group after treatment were both higher than those in the CA330 group (both P<0.01). No serious adverse event occurred in patients in the CA330 group and the OXIRIS group during the treatment process. Conclusion OXIRIS may be better in clearing bilirubin and endotoxin, improving coagulation function, protecting organ function, and regulating oxidative stress response in patients, while CA330 may be more prominent in clearing inflammatory markers and regulating inflammation-related gene expression in patients.