Objective: To investigate the effect and mechanism of Sargassum integerrimum phlorotannins (SIPT) on inhibiting the growth of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer. Methods: NNK-induced A/J mouse lung cancer model was used to evaluate the effect of SIPT on the growth of lung cancer in vivo; the levels of MDA, SOD, and GSH in the serum of mice were detected, and the effect of SIPT on A/J was evaluated; MTT and plate colony formation assay were used to detect the effect of SIPT on NNK-promoted the proliferation of lung cancer cell A549 and NCI-H460; Annexin V-FITC assay was used to detect SIPT on NNK inhibition of lung cancer cell apoptosis; Western blotting method was used to detect the effect of SIPT on the expression of Nrf2-ARE signaling pathway-related proteins in cells. Results: After 8 weeks of intragastric administration of SIPT, the number of lung tumors of mice in the SIPT groups was significantly less than that in the NNK group (P<0.01); the level of MDA in the serum of the mice in the SIPT groups was lower than that in the NNK group (P<0.01), the activities of SOD and GSH were significantly higher than those of the NNK group (both P<0.01). SIPT inhibited the effect of NNK on the proliferation of lung cancer cells (P<0.01) and significantly induced apoptosis (P<0.01). The expression levels of Nrf2, NQO1, HO-1, and GCLC in cells were significantly increased compared with those in the NNK group after 24 h of treatment with SIPT (all P<0.01). Conclusion: SIPT can effectively inhibit NNK-induced lung cancer growth and induce lung cancer cell apoptosis, and its mechanism is related to the activation of Nrf2-ARE signaling pathway.