GATA binding protein 6 (GATA6) is a transcription factor involved in cell fate decision making and tissue morphogenesis and serves a significant role in the progression of a number of types of cancer. The present study aimed to investigate the role and mechanisms underlying the effects of GATA6 in oral squamous cell carcinoma (OSCC). The expression levels of GATA6 were determined in a number of OSCC cell lines and the expression of GATA6 was knocked down to evaluate its role in the proliferation, invasion and migration of OSCC cells. Subsequently, the association between GATA6 and fibronectin 1 (FN1) was investigated using bioinformatics and further verified using dual-luciferase reporter and chromosomal immunoprecipitation assays. Following the overexpression of FN1 in OSCC cells with GATA6 silencing, functional assays were performed to assess the mechanisms underlying GATA6 in OSCC progression. The results of the present study indicated that OSCC cells exhibited markedly upregulated expression levels of GATA6, while knockdown of GATA6 inhibited the proliferation, colony formation, invasion and migration of OSCC cells. In addition, GATA6 regulated FN1 expression levels by binding to the FN1 promoter. The suppressive effects of GATA6 knockdown on the proliferation, colony formation, invasion and migration of OSCC cells were abolished following FN1 overexpression. In conclusion, the findings of the present study demonstrated that GATA6 promoted the malignant development of OSCC cells by binding to the FN1 promotor. These results may contribute to further understanding the pathogenesis of OSCC and provide potential therapeutic targets for the clinical treatment of OSCC.