Tobacco smoking can cause a number of cancers. The role of thromboxane synthase (TxAS) in smoking-related cancers is largely unknown. In this study, 37 pairs of tumor and non-tumor lung tissues of non-small-cell lung cancer, 5 lung cancer cell lines, and a mouse tumor model were used to study TxAS and its related molecules. A mouse model of smoking carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK)-induced lung tumor showed an increase in TxAS. Thromboxane A2 receptor (TP) was aberrant in lung cancer tissues of smokers. TxAS and TP were increased in lung tissues of NNK-treated mice. The in vitro studies showed that TP alpha rather than TP beta promoted tumor growth, and NNK increased TP alpha. NNK-induced TxAS, which depended on activation of cyclooxygenase-2 (COX-2), ERK and NF-kappa B, could be inhibited by miR-34b/c. TP alpha played a positive role in NNK-induced COX-2/ERK/NF-kappa B activation, leading to the upregulation of TxAS expression and thromboxane A2 (TxA2) synthesis. The newly synthesized TxA2 could further activate TP alpha, forming an autoregulatory feedback loop for TP alpha activation. Collectively, NNK promotes lung tumor growth via inducing TxAS and TP alpha, which constitutes an auto-positive feedback loop to exaggerate the growth. This study suggests that TP alpha and TxAS are the ideal targets against smoking-related lung cancer.