Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor in klfs family, is known for its crucial role in regulating cell growth, proliferation, and differentiation. This research aimed to explore the prognostic significance of KLF4 in hepatocellular carcinoma’s (HCC) patients after curative resection and the role of KLF4 in HCC progression. There were 185 HCC patients who had hepatectomy from July 2010 to July 2011 included in this study. KLF4 expression was detected by microarray immunohistochemical technique, western blot, and qRT-PCR. Then, the correlation between the prognosis of patients and KLF4 expression was evaluated based on patients’ follow-up data. The research found KLF4 expression was significantly downregulated in HCC tissues compared to para-tumorous tissues. More importantly, the overall survival rate (OS) and recurrence-free survival rate (RFS) of HCC patients with low KLF4 expression were both significantly decreased compared to those with a high level of KLF4. Further function and mechanism analysis showed that KLF4 could inhibit the proliferation, migration, invasion and epithelial-mesenchymal transition of HCC cells. The study revealed that KLF4 was not only a tumor suppressor in HCC but also can be regarded as a valuable prognostic factor and potential biological target for diagnosis and treatment in HCC patients.