Background: Septic shock is a common systemic inflammatory response syndrome for critical patients in the intensive care unit. Ulinastatin is currently used for the treatment of septic shock. Our study sought to evaluate the efficacy and safety of ulinastatin in the treatment of septic shock patients. Methods: Three English databases (Embase, Medline, and Cochrane Library) and four Chinese databases (China National Knowledge Infrastructure, Wanfang data, SinoMed, and VIP) were searched for published randomized controlled trials. Stata 16.0 software was used to conduct the meta-analysis. Results: A total of 48 articles were included (Chinese article 47, 1 in English). The results show that the treatment of ulinastatin could reduce mortality (risk ratio = 0.63, 95% confidence interval (CI) (0.55, 0.72)), multiple organ dysfunction syndrome (risk ratio = 0.6, 95% CI (0.53, 0.68)), length of intensive care unit stay (mean difference (MD) = -3.92, 95% CI (-4.65, -3.18)), length of hospital stay (MD = -4.39, 95% CI (-6.63, -2.15)) and decrease Acute Physiology and Chronic Health Evaluation II score (MD = -4.55, 95% CI (-5.63, -3.47)) and Sequential Organ Failure Assessment score (MD = -2.02, 95% CI (-2.59, -1.44)) with P < 0.001. Moreover, it lowers TNF-a (standardized mean difference (SMD) = -1.78, 95% CI (-2.24, -1.32)), Interleukin-6 (SMD = -1.17, 95% CI (-1.55, -0.8)), C reactive protein (SMD = -1.49, 95% CI (-1.99, -0.99)), hypersensitive C-reactive protein (SMD = -1.9, 95% CI (-2.87, -0.94)) and procalcitonin (SMD = -0.89, 95% CI (-1.12, -0.67)) levels in the body. Conclusions: Available evidence shows that ulinastatin reduces case mortality rate, multiple organ dysfunction syndrome, length of intensive care unit stay, and length of hospital stay and decreases Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score. Moreover, it also lowers TNF-a, Interleukin-6, C reactive protein, hypersensitive C-reactive protein, and procalcitonin levels in the body. [ABSTRACT FROM AUTHOR]