Oral squamous cell carcinoma (OSCC) is a common head and neck malignant tumour with high incidence and poor prognosis. Arsenic trioxide (ATO) has therapeutic effects on solid tumours. Microwave ablation (MWA) has unique advantages in the treatment of solid tumours. However, the therapeutic mechanism of ATO and MWA, as well as their combined effect on OSCC were largely unelucidated. Cal-27 cell-bearing nude mice were treated with ATO and/or MWA, respectively. RNA sequencing was used to obtain gene expression profiles in tumour tissues of mice treated by ATO or MWA. RNA sequencing results were verified by real-time polymerase chain reaction (PCR). The lncRNA-miRNA-mRNA co-expression network was constructed based on the competitive endogenous RNA (ceRNA) theory. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using differentially expressed genes. The combined effect of ATO and MWA on OSCC was evaluated. Finally, CCK-8 assay, EdU assay and transwell migration assay were performed to detect the effect of HSPA6 on the proliferation and migration of OSCC cells. The reduced volume of tumour tissues was observed in both ATO- and MWA-treated groups. 37.8% decreased in the ATO group and 35.0% in the MWA group. A total of 207 and 539 differentially expressed mRNAs and lncRNAs were identified in the ATO group. And a total of 200 and 522 differentially expressed mRNAs and lncRNAs in the MWA group were identified. The expression levels of 8 genes were verified by real-time PCR. The differentially expressed genes were closely related to "chemical carcinogenesis", "herpes simplex infection", "porphyrin and chlorophyll metabolism", and "MAPK signalling pathway". The lncRNA-miRNA-mRNA co-expression networks were constructed. The combined treatment with ATO and MWA showed a better inhibitive effect on OSCC than either of them. The synergistic effect of ATO and MWA was related to the upregulation of HSPA6. The downregulation of HSPA6 could promote the proliferation and migration of OSCC cells. This study detected the long non-coding RNA and mRNA expression profiles related to the treatment of OSCC and constructed corresponding ceRNA networks. Arsenic trioxide and MWA have a synergistic effect on OSCC, which was related to the upregulation of HSPA6.