Background. The incidence of acute lung injury/acute respiratory distress (ALI/ARDS) is high in sepsis aggravating morbidity and mortality. Glycyrrhizic acid (GA) has pharmacological activities in the treatment of inflammation and antiviral. Materials and Methods. Sepsis rats were constructed by the cecal ligation and puncture (CLP) surgery. After GA (25 and 50 mg/kg) injection, the survival rate, blood oxygen, biochemical indexes, myeloperoxidase (MPO) activity, and wet/dry weight ratio of the lung were observed. The bronchoalveolar lavage fluid was collected to count the cells and measure the level of TNF-α, IL-1β, IL-10, and high mobility group box-1 protein (HMGB1). Lung tissue sections were taken to observe the levels of histopathological injury and apoptosis by HE and TUNEL staining. The levels of HMGB1, TLR4, p-38 MAPK, NF-κB, and ERK1/2 proteins were observed by immunohistochemistry and Western blot. Results. GA treatment improved the survival rate, blood oxygen, ALT, AST, BUN, and Scr of CLP rats. It could advance the MPO activity, the wet/dry weight ratio, histopathological injury, apoptosis, and the IL-10 level in the lung. After GA injection, the number of total cells, neutrophils, and macrophages in the CLP rats was reduced and the levels of TNF-α, IL-1β, HMGB1, TLR4, p-38 MAPK, and ERK1/2 in the CLP rat were also repressed. Conclusions. GA treatment may improve the sepsis-induced ALI/ARDS and inflammation by inhibiting HMBG1. This study provided an experimental basis for the prevention and treatment of ALI/ARDS caused by sepsis.