Oral squamous cell carcinoma (OSCC) is a malignancy that largely impacts the quality of people's daily life. Kallikrein-related peptidase 4 (KLK4) is highly expressed in OSCC; however, its roles in OSCC cells are unclear. In the present study, the effect of KLK4 silencing on the growth of OSCC cells was investigated. Our study showed that the proliferation and colony formation of OSCC cells was inhibited by KLK4 silencing and their cell cycle was arrested. Additionally, apoptosis of OSCC cells was enhanced by KLK4 silencing, with increased protein levels of cleaved PARP, cleaved caspase-3, Bax and decreased levels of Bcl-2. KLK4 silencing inhibited the Wnt/β-catenin signaling pathway, as evidence by decreased protein levels of Wnt1, β-catenin, reduced GSK-3β phosphorylation as well as decreased levels of cyclinD1 and c-myc proteins. We further showed that Wnt/β-catenin activator reversed the effects of KLK4 silencing on the proliferation and apoptosis of OSCC cells. We concluded that KLK4 silencing inhibited the growth of OSCC cells through Wnt/β-catenin signaling pathway, suggesting that KLK4 may become a promising therapeutic target for the treatment of OSCC.