Objective The long non-coding RNA Growth-arrest-specific transcript 5 (GAS5) has been extensively linked with the ability of cancer cells to resist chemotherapeutic interventions. This prospective study aimed to investigate the role of GAS5 in oral squamous cell carcinoma (OSCC), which has been poorly characterized to date. Methods GAS5 and miR-196a expression levels were detected by quantitative real-time PCR analysis. Cisplatin (DDP) sensitivity and apoptosis levels were determined using Cell Counting Kit 8 and flow cytometry, respectively. Luciferase reporter and RNA immunoprecipitation assays were performed to confirm target miRNAs of GAS5. Results We found that GAS5 was expressed at low levels in DDP-resistant OSCC cell lines and tissues, and that GAS5 levels were intricately linked to the survival rates of OSCC patients. GAS5 overexpression led to the recovery of DDP sensitivity in CAL27/DDP cells. Additionally, in both DDP-resistant and -sensitive lines, GAS5 showed a cytoplasmic distribution and downregulated miR-196a in OSCC tissues. Exogenous transfection of miR-196a alleviated the effects of GAS5 on DDP sensitivity, confirming this as the mechanism of chemoresistance. Conclusions These findings may provide new targets for the treatment of chemotherapy-resistant OSCC.