Hepatocellular carcinoma (HCC) is a malignant tumour that poses a serious threat to human health and places a heavy burden on individuals and society. However, the role of GPC1 in the malignant progression of HCC is unknown. In this study, we analysed the expression of GPC1 in HCC, and its association with poor patient prognosis. The effects of GPC1 on the proliferation, invasion and migration of HCC were analysed through cellular functional experiments in vitro and in vivo. Mechanistically, DNA methylation of GPC1 was analysed by DNA extraction, methylation-specific PCR and bisulfite Sanger sequencing (BSP), and the target genes TET1 and miRNA regulating DNA methylation of GPC1 were found through the bioinformatics database. The results revealed that GPC1 was highly expressed in HCC, and its high expression was significantly associated with poor prognosis of HCC patients. Inhibiting the expression of GPC1 can inhibit the proliferation, invasion and migration of HCC cells. GPC1 was hypomethylated in HCC, and its methylation level was regulated by TET1. miR-143-3p can significantly regulated the expression of TET1 and affect the methylation level and protein expression of GPC1. Furthermore, GPC1 also affects the malignant biological behaviour of HCC by regulating the expression of Hippo signalling pathway. In summary, miR-143-3p regulates the expression of TET1, affects the expression of GPC1 through DNA methylation and regulates the malignant progression of HCC via Hippo signalling pathway.