Septic shock is the most severe complication of sepsis occurs when body has an overwhelming response to infection, making it the most prevalent cause of deaths in surgical intensive‐care units. Therefore, it is urgent to understand its pathogenesis and develop new therapeutic candidate drugs for septic shock. Here, we explored the effect of FP7, an antagonist of Toll‐like receptor 4 (TLR4), in the septic shock. First, we injected mice with FP7 and found that FP7 had no effect on immune cells. Then, bone marrow‐derived macrophages (BMDMs) isolated from mice were pretreated with FP7 followed by lipopolysaccharide (LPS) stimulation, and FP7 specifically suppressed LPS‐induced inflammatory responses in BMDMs via Nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐κB) signaling pathway, with no effect on other TLRs‐mediated inflammations. Finally, we injected mice with LPS and D‐galactosamine to induce septic shock, followed by the treatment of FP7, and FP7 significantly increased survival rate, improved lung necrosis, and inhibited the secretions of proinflammatory cytokines in the mice with septic shock. Therefore, our study suggested that FP7 had a protective role in septic shock and it might serve as a promising therapeutic candidate drug to treat septic shock.