Selenium (Se) is important in many physiological processes, such as antioxidant processes and inflammation. The aim of our experiments was to investigate the molecular mechanism that selenomethionine could reduce the lipopolysaccharide (LPS)-induced inflammation by inhibiting the TLR4-NF-κB-NLRP3 signaling pathway. Eighty broilers were randomly and evenly divided into two groups, giving normal Se content diets (Con group, 0.2 mg Se/kg diet) and Se-rich basal diets (Se group, 0.5 mg selenomethionine/kg diet) for 90 days. Se-rich basal diets were based on 0.2 mg/kg sodium selenite contained. Five hours before euthanized, 20 broilers were randomly selected from each group and given lipopolysaccharide (200 μg/kg BW) by intraperitoneal injection, Con+LPS group and Se+LPS group, respectively. The Con group and Se group were given equal saline by intraperitoneal injection. We observed the microscopic pathological changes of liver tissue detected oxidative stress by kit and detected the expression of inflammatory factors, heat shock protein (HSP), and nod-like receptor protein 3 (NLRP3)-related genes by qRT-PCR and Western blot. With the microscope, we found the Con+LPS group had obvious inflammatory lesions such as sinusoidal congestion, but the damage was significantly alleviated in the Se+LPS group. In the Con+LPS group, the activity of GSH-Px and the content of GSH were significantly decreased compared with those in the Con group; however, they are increased in the Se group and in the Se + LPS group. Inflammatory factors (MyD88, NF-κB, TNF-α, IL-1β, IL-6, IL-12, IL-18, iNOS, and COX-2), heat shock proteins (HSP27, HSP60, HSP70, and HSP90), and the expression of NLRP3 and caspase-1 increased in the Con+LPS group compared with those in the Con group, while they were lower in the Se+LPS group than in the Con+LPS group. We concluded that selenomethionine inhibits the LPS-induced inflammation of liver tissue via suppressing the TLR4-NF-κB-NLRP3 signaling pathway.