Abstract YEATS domain containing 2 (YEATS2), it may function as a proto-oncogene. This study aims to investigate if YEATS2 correlates with prognosis in hepatocellular carcinoma. The prognostic landscape of YEATS2 and its relationship with expression in hepatocellular carcinoma were deciphered with public databases, RT-qPCR and western-blot in tissue samples. The expression profiling and prognostic value of YEATS2 were explored using UALCAN, TIMER, OncoLnc database. Transcription and survival analyses of YEATS2 in hepatocellular carcinoma were investigated with cBioPortal database. The STRING database was explored to identify molecular functions and signaling pathways downstream of YEATS2. YEATS2 expression was significantly higher in hepatocellular carcinoma compared with adjacent non-malignant tissues. Promoter methylation of YEATS2 exhibited different patterns in hepatocellular carcinoma. High expression of YEATS2 was associated with poorer survival. Mechanistically, YEATS2 was involved in mediating multiple biological processes including morphogenesis and migration.