It had been demonstrated that apolipoprotein M (apoM) is an important carrier of sphingosine-1-phosphate (S1P) in blood, and the S1P has critical roles in the pathogenesis of sepsis-induced acute lung injury (ALI). In the present study, we investigated whether apoM has beneficial effects in a mouse model after lipopolysaccharide (LPS)-induced ALI. Forty-eight mice were divided into two groups: male C57BL/6 wild-type (apoM(+/+)) group (n = 24) and apoM gene-deficient (apoM(-/-)) group (n = 24) and then randomly subdivided into four subgroups (n = 6 each) according to different intraperitoneal (i.p.) injection: control group, W146 group, LPS group, and LPS + W146 group. Serum levels of interleukin-1 beta (IL-1 beta) and mRNA levels of IL-1 beta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), lung histology, wet/dry weight ratio, and immunohistochemistry were measured at 3 h after the baseline and compared in each group. Our results clearly demonstrated that IL-1 beta mRNA levels and other inflammatory biomarkers were significantly increased in the lungs of LPS-induced ALI apoM(-/-) mice compared to those of the apoM(+/+) mice. Moreover, when apoM(+/+) mice were treated with W146, a S1P receptor (S1PR1) antagonist, these inflammatory biomarkers could be significantly upregulated by LPS-induced ALI. Therefore, it suggests that apoM-S1P-S1PR1 signaling might underlie the pathogenesis of ALI and apoM could have physiological benefits to alleviate LPS-induced ALI.