Long non-coding RNAs (lncRNAs) have been consistently demonstrated to be involved in oral squamous cell carcinoma (OSCC) as either tumor oncogenes or tumor suppressors. However, the underlying mechanisms of OSCC tumorigenesis and development have not yet been fully elucidated. The expression profiles of mRNAs and lncRNAs in OSCC were analyzed by a microarray assay. To verify the results of the microarray, 10 differentially expressed lncRNAs were randomly selected and measured by quantitative RT-PCR (qRT-PCR). Gene Ontology (GO) and metabolic pathway analyses were performed to analyze gene function and identify enriched pathways. Subsequently, two independent algorithms were used to predict the target genes of the lncRNAs. We identified 2,294 lncRNAs and 1,938 mRNAs that were differentially expressed in all three OSCC tissues by a microarray assay. Through the construction of co-expression networks of differentially expressed genes, 4 critical lncRNAs nodes were identified as potential key factors in the pathogenesis of OSCC. Expression of the 4 critical lncRNA nodes was not associated with age, sex, smoking or tumor location (P>0.05) but was positively correlated with clinical stage, lymphatic metastasis, distant metastasis and survival status (P<0.05). Kaplan-Meier analysis demonstrated that low expression levels of these 4 critical lncRNA nodes contributed to poor median progression-free survival (PFS) and overall survival (OS) (P<0.05). GO and pathway analyses indicated that the functions and enriched pathways of many dysregulated genes are associated with cancer. Potential target genes of dysregulated lncRNAs were enriched in 43 metabolic pathways, with cancer pathways being the primary enrichment pathways. In summary, we analyzed the profile of lncRNAs in OSCC and identified the functions and enriched metabolic pathways of both dysregulated mRNAs and the target genes of dysregulated lncRNAs, providing new insights into molecular markers and therapeutic targets for OSCC.