Objective  To investigate the effects of continuous veno-venous hemodiafiltration (CVVHDF) combined with hemoperfusion (HP) on the clearance of inflammatory cytokines and prognosis in children with septic shock. Methods  This study was a prospective randomized controlled trial. The subjects were children aged 0-14 years diagnosed with septic shock who were admitted to the Pediatric Intensive Care Unit (PICU) of the First Affiliated Hospital of Henan Medical University (formerly Xinxiang Medical University) from October 2021 to July 2024. They were randomly assigned (1:1 ratio) via a random number table to either a blood purification treatment group or a conventional treatment group. The following parameters were observed before treatment and 72 hours after treatment: serum levels  of inflammatory cytokines including NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome in peripheral blood, as well as total hospital length of stay, PICU length of stay, and 28‑day clinical outcomes. Results  A total of 33 children were enrolled in the blood purification group and 33 in the conventional treatment group. Before treatment, there were no significant differences between the two groups in NLRP3 (t=-1.256, P=0.214), white blood cell count (WBC) (t=-1.086, P=0.282), procalcitonin (PCT) (t=0.913, P=0.365), interleukin‑6 (IL‑6) (t=0.731, P=0.467), C‑reactive protein (CRP) (t =0.701, P=0.486), or blood lactate (Lac) (t=-0.942, P=0.350). After treatment, all the above parameters were significantly lower in the blood purification group than in the conventional treatment group (NLRP3:t=-7.597, P<0.001; WBC:t=-3.034, P=0.004; PCT: t=-4.930,P＜0.001; IL‑6: t=-4.357, P＜0.001; CRP: t=-5.002, P<0.001; Lac: t=-2.102, P=0.040). Receiver operating characteristic (ROC) curves and areas under the curve (AUC) showed that NLRP3 (AUC=0.842, 95% CI: 0.704～0.980, P=0.001), IL‑6(AUC=0.741, 95% CI:0.510～0.971, P=0.021), and Lac (AUC=0.784, 95% CI: 0.627～0.940, P=0.007) had certain predictive value for 28‑day mortality. The 28‑day mortality rate in the blood purification group was significantly lower than that in the conventional treatment group (3.0% vs. 24.2%, χ²=4.632, P=0.031), and both total hospital stay (t=-2.157, P=0.037) and PICU stay (t=-2.108, P=0.039) were shortened.  Conclusion  Compared with conventional treatment, CVVHDF combined with HP can more effectively clear inflammatory cytokines in children with septic shock, reduce mortality, shorten hospital stay, and improve prognosis. NLRP3, IL‑6, and Lac are good predictors of mortality in these children.