<p>Cisplatin (DDP) is a commonly used chemotherapeutic drug for oral squamous cell carcinoma (OSCC) clinical treatment. However, DDP resistance often brings about treatment failure. This study aims to demonstrate the mechanism of JARID1B in DDP-resistance of OSCC cells. Tissue specimens of OSCC and adjacent normal tissues were collected and OSCC cell lines resistant to DDP were established, followed by measurement of JARID1B, H3K4me3, miR-495-3p and FUBP1 levels. CCK-8 was used to detect the IC₅₀ value. Cell proliferation and apoptosis were assayed. The enrichment of JARID1B and H3K4me3 on the miR-495-3p promoter was assayed via ChIP. The binding between miR-495-3p and FUBP1 was confirmed via dual-luciferase reporter assay. Results showed that JARID1B and FUBP1 were highly expressed in OSCC, while miR-495-3p was lowly expressed. After inhibiting JARID1B expression in OSCC cells, cell proliferation was decreased, apoptosis was increased, and cell resistance to DDP was reduced. JARID1B downregulation increased H3K4me3 levels and promoted miR-495-3p expression, which promoted the binding of miR-495-3p to FUBP1, thus downregulating FUBP1 transcription. FUBP1 overexpression or miR-495-3p downregulation partially reversed the inhibitory effect of JARID1B downregulation on DDP resistance of OSCC cells. In conclusion, JARID1B-mediated H3K4me3 demethylation promotes DDP resistance in OSCC cells through the miR-495-3p/FUBP1 axis.</p>