Lung adenocarcinoma (LAC) is currently the predominant histological subtype of lung cancer. Despite recent advancement in targeted therapies, the average 5-year survival rate is only 15%, highlighting the need to identify previously unrecognized molecular events that propel cancer development. Herein, we showed knockdown of 14-3-3 zeta suppresses cell proliferation, migration and invasion capability of A549 and H1299 cells. MUC1 was then identified as a novel target of 14-3-3 zeta protein. Overexpression of MUC1 is found to induce epithelial-mesenchymal transition and promote metastasis of lung cancer cells, while knockdown of 14-3-3 zeta can completely abolish the oncogenic function of MUC1. Furthermore, we unraveled a novel mechanism that 14-3-3 zeta activates NF-kappa B signaling pathway, and therefore enhanced MUC1/NF-kappa B feedback loop to upregulate MUC1 expression. From a clinical point of view, we evaluated the expression of 14-3-3 zeta and MUC1 in GSE68465 datasets, in which high expression of 14-3-3 zeta and MUC1 emerged as poor prognostic factors in LAC patients. In conclusion, we provide novel evidence that 14-3-3 zeta regulates MUC1 through MUC1/NF-kappa B feedback loop. 14-3-3 zeta and MUC1 is a promising prognostic biomarker for lung cancer patients and therapeutic targeting of 14-3-3 zeta and MUC1 may be a potential treatment option for patients with LAC.