Sepsis is a severe, life-threatening condition caused primarily by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. The present study investigates the protective effect of L-lysine against sepsis-induced acute lung injury (ALI) in a lipopolysaccharide-induced mouse model. In the present study, mice were divided into sham, control, 5 mg/kg body weight L-lysine, and 10 mg/kg body weight L-lysine treatment groups. At the end of the treatment period, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. The effects of L-lysine on the cellular architecture of lung tissue were also evaluated. L-Lysine treatment significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts. It also increased the levels of reduced glutathione and the activities of glutathione peroxidase, superoxide dismutase, and catalase. A normal cellular architecture was noted in mice in the sham group, whereas proinflammatory changes such as edema and neutrophilic infiltration were detected in mice in the control group. L-lysine significantly ameliorated these proinflammatory changes. Taking all these data together, it is suggested that the L-lysine was effective against sepsis-induced ALI.