Objective: To investigate the effect of early plasma exchange (PE) combined with continuous veno-venous hemofiltration (CVVH) on vasoactive-inotropic score and inflammatory markers in children with septic shock. Methods: A retrospective analysis was conducted on the clinical data of 229 children with septic shock. Based on the treatment methods, and on the basis of standard septic shock treatment, 112 children treated with CVVH were included in the control group, and 117 children treated with early PE combined with CVVH were included in the combined group. The shock correction time, hemodynamic indicators [mean arterial pressure (MAP), capillary refill time (CRT)], vasoactive-inotropic score, lactate clearance rate, pediatric Sequential Organ Failure Assessment (pSOFA) score, inflammatory factors [serum C-reactive protein (CRP), procalcitonin (PCT)], incidence of adverse events, and hospitalization and prognosis indicators were compared between the two groups. Results: The shock correction time in the combined group was shorter than that in the control group (P<0.05), the MAP level after 72 h of treatment in the combined group was higher than that in the control group, and the improvement in CRT was better than that in the control group (P<0.05). The vasoactive-inotropic score at 6, 12, 24, 48, 72 h, and 7 d after treatment in the combined group was lower than that in the control group (P<0.05), the lactate clearance rate at 6, 24, and 72 h after treatment in the combined group was higher than that in the control group (P<0.05), the pSOFA score at 24, 48, 72 h, and 7 d after treatment in the combined group was lower than that in the control group (P<0.05), the serum inflammatory indicators PCT and CRP levels after 72 h of treatment in the combined group were lower than those in the control group (P<0.05). There was no significant difference in the incidence of adverse events and 28-day mortality between the two groups during treatment (P>0.05). The PICU hospitalization time and total hospitalization time in the combined group were shorter than those in the control group (P<0.05). Conclusion: Early PE combined with CVVH in the treatment of children with septic shock can shorten the shock correction time, improve hemodynamic status, reduce vasoactive drug dependence, reduce the body’s inflammatory response, and shorten the length of hospital stay without increasing the risk of adverse events.