The purpose of the present study was to identify the potential function of Kruppel-like factor 5 (KLF5) in thyroid cancer and investigate the underlying mechanisms. The protein levels of KLF5 in 98 thyroid cancer tissues were analyzed using an immunohistochemistry assay. SW579 cells transfected with small interfering RNA against KLF5 and B-CPAP cells transfected with KLF5 expressing vectors were used for functional studies. Western blot analysis, immunofluorescence and co-immunoprecipitation assays were used to investigate the mechanisms of KLF5. In vivo tumorigenicity was assessed using a subcutaneous xenograft experiment. The results revealed that KLF5 was highly expressed in thyroid cancer tissues and associated with lymph node metastasis. Knockdown of KLF5 in SW579 cells suppressed proliferation, anchorage-independent growth, migration and invasion in vitro, while the overexpression of KLF5 resulted in opposite effects in B-CPAP cells. Mechanistically, it was demonstrated that KLF5 promoted the cytoplasm-nuclear translocation of nuclear factor-κB. Additionally, it was revealed that insufficient F-box/WD repeat-containing protein 7 expression may be responsible for the dysfunction of KLF5 in thyroid cancer. These results revealed that KLF5 promotes the tumorigenesis and metastasis of thyroid cancer cells and may be a potential therapeutic target in patients with thyroid cancer.