Objective To explore the predictive efficacy of serum Pentraxin 3 (PTX3) combined with Sestrin2 for disease outcome in patients with septic shock.Methods A total of 122 patients with septic shock admitted to our hospital from May 2020 to May 2023 were selected as the study group, followed up for 28 days, and divided into survival group (n = 83) and death group (n = 39) according to the prognosis. In addition, 150 healthy people who underwent health checkup in our hospital during the same period were included as the control group. Serum levels of PTX3 and Sestrin2 were detected by enzyme-linked immunosorbent assay, and the predictive values of serum PTX3 and Sestrin2 for prognosis of patients with septic shock were assessed by receiver operating characteristic (ROC) curves. The factors affecting the prognosis of patients with septic shock were analyzed by multivariable stepwise Logistic regression.Results Serum levels of PTX3 and Sestrin2 in the study group were higher than those in the control group (P < 0.05). Serum levels of PTX3 and Sestrin2 in the death group were higher than those in the survival group (P < 0.05). ROC curve analysis showed that the area under the curve (AUC) of PTX3 combined with Sestrin2 for predicting the prognosis of patients with septic shock was the largest, which was 0.904 (95% CI: 0.853, 0.955), with a specificity of 85.68% (95% CI: 0.838, 0.948) and a sensitivity of 84.26% (95% CI: 0.884, 0.932). The proportion of patients with the age ≥ 60 years, SOFA score and APACHEⅡ score in the death group were higher than those in the survival group (P < 0.05), and the leukocyte count and serum levels of creatinine and procalcitonin in the death group were higher than those in the survival group (P < 0.05). The multivariable stepwise Logistic regression analysis (inclusion of variables with α < 0.05 and exclusion of variables with α > 0.10) revealed that high SOFA score [O^R = 2.022 (95% CI: 1.443, 2.832) ], high level of procalcitonin [O^R = 2.261 (95% CI: 1.577, 3.243) ], PTX3 ≥ 94.72 ng/mL [O^R = 3.019 (95% CI: 1.939, 4.702) ], and Sestrin2 ≥ 15.87 ng/mL [O^R = 2.617 (95% CI: 1.727, 3.965) ] were the prognostic factors for patients with septic shock (P < 0.05).Conclusion Serum PTX3 and Sestrin2 are highly expressed in patients with septic shock, and are biomarkers for predicting the prognosis of patients with septic shock, with the combination of the two indicators yielding higher predictive efficacy.