Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical common disease caused by various pathological factors and can induce serious complications. There is still no specific and effective method for the treatment of ALI/ARDS. Mesenchymal stem cells (MSCs) have been one of the treatment methods for ALI, which can regulate related signal pathways such as PI3K/AKT, Wnt, and NF-ΚB to reduce inflammation. MSCs exist in various tissues and can self-renewal and differentiation, which can be activated by specific substances or environments and home to the site of tissue damage, where they differentiate into new tissue cells and repair the damage. Both exosomes and cytokines involving the paracrine mechanism of MSCs have benefits in treating ALI. Lung organoids produced by 3D culture technology can simulate the lung's characteristics and help research the pathophysiological process of ALI. This review summarizes the mechanisms by which MSCs treat ALI/ARDS and expects to use 3D models for future challenges in this field.