Hepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we have developed a high content RNA-FISH-based imaging assay that allows, for the first time, the investigation of the entry pathways of both naked and enveloped HEV particles. Surprisingly, we obtained compelling evidence that integrin α3, previously implicated in naked HEV cell entry, is not expressed in various HEV-permissive cells. Instead, we have identified integrin β1 (ITGB1) as the key player in pairing with exchangeable α-integrins to mediate naked HEV cell entry. Our results indicate that the interaction with ITGB1 facilitates naked HEV entry through the recycling endosome. In contrast, enveloped HEV particles do not interact with ITGB1 and rather use the classical endocytic route via the early endosome. Importantly, both forms of HEV require endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.