Objective To observe the protective effect and molecular mechanism of C-phycocyanin (CPC) on acute lung injury (ALI) in septic rats. Method 75 SD rats were randomly divided into control group, model group and CPC group. Cecal ligation and puncture was used to establish a septic acute lung injury rats (model group). For the CPC groups, septic acute lung injury rats were administrated by 20, 40 and 60 mg/kg CPC by intraperitoneal injection. 72 h after the operation, serum and lung tissue were obtained, the wet to dry weight ratio, the content of TNF-α、IL-6 and IL-10 in bronchoalveolar lavage fluid, the activity of myeloperoxidase (MPO) was analyzed. Expression of heme oxygenase (HO)-1,activation of nuclear factor erythroid 2-related factor 2 (Nrf 2) and nuclear factor-kappa B (NF-B) were detected by Western blot. Superoxide and Nitrite/Nitrate Level production in Lungs and bronchoalveolar lavage fluid were measured by chemiluminescence and reduction method, respectively. Results Treatment with CPC significantly inhibited septic-induced inflammatory responses including elevation of superoxide formation, myeloperoxidase activity, leucocytes and protein infiltration in lung tissues, and production of proinflammatory cytokine, and nitrite/nitrate in bronchoalveolar lavage fluid (P<0.05). In addition, CPC could activate Nrf 2 and induce HO-1 expression, and inhibit NF-B activation in ALI rats. However, blocking HO-1 activity by tin protoporphyrin IX (SnPP), an HO-1 inhibitor, markedly abolished these beneficial effects of CPC in septic-induced ALI. Conclusion The protection mechanism of CPC may be through HO-1 induction and suppressing of NF-kB-mediated inflammatory responses.