The prognosis of oral squamous cell carcinoma (OSCC) patients remains unclear, and a better understanding of the underlying molecular mechanisms is urgently required. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), renamed KDM8, has been implicated in tumorigenesis, circadian rhythm modulation, embryological development, and osteoclastogenesis. In the present study, we found that JMJD5 was over-expressed in patients with OSCC by real-time quantitative PCR (qPCR), western blot and immunohistochemical assays. When knockdown using small interfering RNA (siRNA) in OSCCs, JMJD5 was exhibited to be important for sustaining cell migration and invasion. JMJD5-knockdown increased E-cadherin expressions, and decreased N-cadherin and Vimentin expression levels in OSCC cells. Further, apoptosis was induced by JMJD5-silence through both the intrinsic and extrinsic pathways, as evidenced by the increased cleavage of Caspase-8/-9/-3 and PARP. Meanwhile, p53 expression levels were also up-regulated by JMJD5-knockdown. Suppressing p53 expressions with its inhibitor, PFTα, blocked apoptotic response in JMJD5-silenced cells. JMJD5 inhibition-induced decrease of nuclear factor-kappaB (NF-κB) was rescued by pifithrin-α (PFTα) pre-treatment. Consistently, over-expressing JMJD5 decreased p53, cleaved Caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1), whereas increased nuclear NF-κB expressions in OSCC cell lines. More importantly, targeting JMJD5 reduced xenograft tumor growth in vivo through the same molecular mechanisms evidenced in vitro. Thus, the data supplied mechanistic insights into the effects of JMJD5 on the modulation of OSCC development, illustrating that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression.