Abstract: Traf2- and Nck-interacting kinase (TNIK) is closely related to the cancer occurrence, development, and prognosis. TNIK plays an important role in regulating Wnt/β-catenin pathway, thus becoming a potential target for cancer treatment. Various small-molecule TNIK inhibitors with diverse structures and potent in vitro activities have been developed to treat tumors. However, no TNIK inhibitor has entered clinical phase mainly due to poor selectivity, toxicity, and unsatisfied in vivo anti-tumor efficiency. This review summarizes the research progress of small molecule inhibitors targeting TNIK, with the aim of giving some guidance for future research and development of small-molecule inhibitors.