Background: The immune system plays a major role in pulmonary fibrosis. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of innate immunity with remarkable immune suppressive functions. We hypothesize that the strong anti-inflammatory activity of MDSCs may dampen pulmonary fibrosis by inhibiting local inflammation and its transition to lung fibrosis. Aim: Here, we aim to investigate the emergence of both polymorphonuclear (PMN)- and monocytic (M)-MDSCs and their pattern of generation, activity and recruitment in pulmonary fibrosis. Method: Murine model was performed by administration of bleomycin in C57BL/6 mice. Immunological, histopathological and clinical changes of mice respiratory tract were investigated at days 3, 7, 14, and 21 after bleomycin challenge. Results: Strikingly, we found entirely different pattern of PMN- and M-MDSCs generation and recruitment after bleomycin challenge. The number of PMN-MDSCs was increased on day 3 reaching a maximum on day 21 after bleomycin challenge. However, while the number of M-MDSCs were higher on day 3, their numbers decreased over time reaching to the minimum on day 21. The suppressive activity of PMN-MDSCs was mainly pronounced on day 3, but M-MDSCs retained their suppressive activity from day 3 to day 21. The changes in the number and activity of MDSCs were also correlated with lung histopathological and respiratory mechanics changes. Conclusion: We showed that the number and activity of PMN- and M-MDSCs are different from each in acute inflammatory and fibrotic stages. These findings suggest that MDSCs are involved in modulating the immunological, histopathological and functional changes in pulmonary fibrosis.