Objective: To investigate the clinical efficacy of vasopressin combined with targeted resuscitation in septic shock with acute kidney injury. Methods: A retrospective study was conducted on 86 patients with septic shock complicated with acute kidney injury admitted from June 2020 to April 2025. The patients were divided into two groups according to the treatment method: the conventional group (n=43), which received conventional treatments such as early infection control, target oriented resuscitation, norepinephrine, and renal replacement therapy. The experimental group (n=43) received vasopressin treatment in addition to the conventional group. Compare the MAP compliance time, microcirculation blood flow index, extravascular lung water index, renal function indicators before and after treatment, inflammation and endothelial injury indicators, clinical prognosis, and incidence of adverse events between two groups. Results: The MAP reaching the standard time and extravascular lung water index in the experimental group were lower than those in the control group, while the microcirculation blood flow index was higher than that in the control group (P<0.05); 72 hours after treatment, both groups showed an increase in urine volume, with the experimental group being higher than the control group. Blood creatinine, NGAL, and cystatin C decreased, with the experimental group being lower than the control group (P<0.05); 72 hours after treatment, the levels of IL-6, TNF-α, vWF, and sTM decreased in both groups, with the experimental group lower than the control group (P<0.05); There was no significant difference in the incidence of arrhythmia and mesenteric ischemia related adverse events between the two groups of patients (P>0.05). The 28 day mortality rate, ICU stay, and mechanical ventilation time in the experimental group were lower than those in the conventional group (P<0.05). Conclusion: The combination of vasopressin and targeted resuscitation in patients with septic shock and acute kidney injury can significantly improve their hemodynamic stability, promote renal function recovery, inhibit inflammation and endothelial injury, and further improve their clinical prognosis without increasing the risk of adverse events.