Significant advances in the treatment of non-small cell lung cancer (NSCLC) have been made over the past decade, and they predominantly involve molecular targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. However, despite the initial good response, drug resistance eventually develops. The Wnt signaling pathway has recently been considered important in embryonic development and tumorigenesis in many cancers, particularly NSCLC. Moreover, the aberrant Wnt pathway plays a significant role in NSCLC and is associated with cancer cell proliferation, metastasis, invasion and drug resistance, and the suppression of canonical or noncanonical Wnt signaling through various biological or pharmacological negative regulators has been proven to produce specific anticancer effects. Thus, blocking the Wnt pathway via its negative regulators may overcome the resistance of current treatment methods and lead to new treatment strategies for NSCLC. Therefore, in this review, we summarize recent studies on the role of negative regulators in Wnt signaling in NSCLC and the therapeutic potency of these molecules as agents and targets for NSCLC treatments.