Our aim was to investigate the effects of phycocyanin (PC) on bleomycin (BLM)-induced pulmonary fibrosis (PF). In this study, C57 BL/6 wild-type (WT) mice and toll-like receptor (TLR) 2 deficient mice were treated with PC for 28 days following BLM exposure. Serum and lung tissues were collected on days 3, 7 and 28. Data shows PC significantly decreased the levels of hydroxyproline (HYP), vimentin, surfactant-associated protein C (SP-C), fibroblast specific protein-1 (S100A4) and α-smooth muscle actin (α-SMA) but dramatically increased E-cadherin and podoplanin (PDPN) expression on day 28. Moreover, PC greatly decreased the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) at the earlier time. Reduced expression of key genes in the TLR2 pathway was also detected. Compared with WT mice, TLR2-deficient mice exhibited less injury, and the protective effect of PC was partly diminished in this background. These data indicate the anti-fibrotic effects of PC may be mediated by reducing W/D ratio, MPO, IL-6, TNF-α, protecting type I alveolar epithelial cells, inhibiting fibroblast proliferation, attenuating epithelial-mesenchymal transitions (EMT) and reducing oxidative stress. The TLR2-MyD88-NF-κB pathway plays an important role in PC-mediated reduction in pulmonary fibrosis.