Background Lung injury and pulmonary fibrosis are common sequelae of severe and acute lung disease, including coronavirus disease 2019 (COVID-19), for which there are presently no effective drugs. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have the potential to treat lung injury and pulmonary fibrosis. However, the best administration route, timing, and frequency remain unclear. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and pulmonary fibrosis. Methods Here, the best treatment scheme of IMRCs for pulmonary fibrosis was evaluated. In a mouse pulmonary fibrosis model induced by bleomycin (BLM), IMRCs were administered by single or double intravenous or tracheal injection on the first and seventh days after bleomycin injection. Results Intravenous infusion of IMRCs improved the survival rate, body weight, and Ashcroft and Szapiel scores of model mice more effectively than intratracheal infusion, including more profound suppression of lung inflammation and fibrosis. Moreover, earlier timing of administration and more frequent administration were beneficial to improve the therapeutic effects. Indeed, early administration of two infusions better improved body weight, the lung organ coefficient, pulmonary ventilation and diffusion functions, and pulmonary fibrosis; increased numbers of alveolar type I and type II epithelial cells; and inhibited macrophage infiltration. Conclusion This study provides basic scientific evidence for the clinical application of stem cell therapy products to treat lung diseases including COVID-19.