Recently, studies suggested that the mesenchymal stem cells (MSCs) have anti-inflammatory and immune-modulatory roles in the induced acute lung injury in mice via controlling innate, humoral, and cell-mediated immunity. Sixty adult male mice were divided equally into three groups. Group A (control group) received an intraperitoneal (IP) phosphate-buffered saline. Group B was injected IP with lipopolysaccharide (LPS). Group C was injected IP with LPS, followed after 2 h by intravenous labeled bone marrow-derived MSCs (BM-MSCs). The plasma and bronchioalveolar lavage (BAL) fluid were collected at 12, 24, and 72 h postinjection. Estimation of total cell and neutrophils count and immunoglobulin M (IgM) in BAL fluid was performed. Enzyme-linked immunosorbent assay (ELISA) was used to analyze tumor necrosis factor-α (TNF-α) that is a proinflammatory cytokine and interleukin-10 (IL-10), which is an anti-inflammatory cytokine, in plasma. Lung samples were collected for histopathological examination at 12, 24, 72 h, and 1 week postinjection. Decreased TNF-α and increased IL-10 levels in the plasma of MSC-treated group compared to the LPS-infected group were observed. Also, decreased IgM level in BAL fluid of the MSC-treated group after 72 h compared to the LPS-infected group was detected with a resolution of inflammation and improvement in lung injury. Moreover, MSC-treated group showed a reduction in total leukocyte count and neutrophil percentage in comparison to control and LPS-infected groups. Histopathological improvement was detected in MSC-treated group as well. In conclusion, systemic MSCs injection has an anti-inflammatory and immune-modulatory effect in LPS-induced acute lung injury in mice.