Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague-Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS.In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups.LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen.Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1β.