Background: Nicotine, a major component of cigarette smoke, plays an important role in the development of cardiovascular disease and lung cancer in smokers. The aim of the present work was to investigate protective activity of Spirulina platensis (SP) extract against lung toxicity induced by nicotine in adult rats. Materials and Methods: Thirty six adult albino rats weighing around 150 ±10 g were used for the evaluation of lung protective activity of SP (3% and 6%) against nicotine-induced lung toxicity in rats. Results: The daily oral administration of the SP (3% and 6%) for 30 days to rats treated with nicotine (2.5 mg/kg.b.w.) resulted in a significant improve in plasma cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol as well as serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and growth factor (TGF)-β1 in nicotine treated groups rats. On the other hand, oral administration of SP (3% and 6%) elevated the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total protein kinase-1 (Akt-1) as well as reduced the level malondialdehyde (MDA) in lung rats treated with nicotine. In addition, SP reduced the expression of lung inducible nitric oxide synthase (iNOS) and mitogen-activated protein kinase (p38-MAPK) levels as compared to nicotine treated control group. Also, SP (3% and 6%) almost normalized these effects in the histoarchitecture of the lung. Conclusion: The obtained biochemical, molecular biology and histological results of this study proved the lung protective activity of SP (3% and 6%) against nicotine induced lung toxicity in rats.