Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Using proteomics and biochemical approaches, Agrin was shown to be overexpressed and secreted in HCC. Functionally, Agrin enhances cellular proliferation, migration and oncogenic signalling. Mechanistically, Agrin’s extracellular matrix sensor activity provides oncogenic cues in tumorigenesis. Agrin signalling through Lrp4-muscle-specific tyrosine kinase (MuSK) forms a critical oncogenic axis. Importantly, antibodies targeting Agrin reduced oncogenic signalling and tumour growth in vivo. Therefore, Agrin is frequently upregulated and important for oncogenic property of HCC, and is an attractive target for antibody therapy of HCC.