Histone modifications regulate several biological processes that are critical to cancer development, from cell cycle, DNA damage repair, chromatin compression, to transcriptional regulation. Lysine methyltransferase 5C (KMT5C) is a trimethyltransferase of histone H4 and lysine 20 (H4K20me3) and has been reported to function vary in different types of cancer. However, the role of KMT5C in oral squamous cell carcinoma (OSCC) is unknown. By analyzing the expression of KMT5C in 32 paired OSCC and normal specimens, we first found that KMT5C expression was decreased in OSCC samples. For TNM and T stages, patients from stage I and II showed high expression of KMT5C, while patients from stage III and IV tended to have low expression of KMT5C. KMT5C overexpression significantly retarded the growth and metastasis of OSCC cells in vitro and in vivo, whereas KMT5C knockdown had opposite effects. Notably, in OSCC cells, KMT5C overexpression significantly decreased uridine phosphorylase 1 (UPP1) expression, which was overexpressed in OSCC cells and associated with lymph node metastasis and poor overall survival of OSCC patients. We further demonstrated that overexpression of KMT5C increased the H4K20me3 modification of the UPP1 promoter, leading to transcriptional inhibition. Additionally, transcription factor nuclear receptor subfamily 2 group C member 2 (NR2C2) was responsible for recruiting KMT5C to the UPP1 promoter to achieve H4K20me3 modification of UPP1. Alterations induced by KMT5C knockdown were partly reversed by UPP1 inhibition. Overall, we demonstrate that KMT5C, recruited by NR2C2, suppresses OSCC progression by inhibiting UPP1 transcription in a H4K20me3-dependent way.