To the best of our knowledge, our study is the first to demonstrate the direct binding of human miR-375 to the 3′-UTR of KLF5. Furthermore, the miR-375 mimic significantly reduced KLF5 mRNA and protein levels, resulting in improved proliferation in OSCC cells, while inhibition of miR-375 resulted in the opposite effect, suggesting that miR-375 may regulate cell proliferation via KLF5 in oral cancer progress. This evidence concerns the gene KLF5 and lip and oral cavity carcinoma.