Infection by hepatitis E virus (HEV) via the oral route causes acute hepatitis. Extra-hepatic manifestations of HEV infection may stem from various causes; however, its distribution in organs such as the liver, as well as the mechanisms underlying HEV-induced cell injury, remain unclear. The objective of this study was to determine the chronological distribution of HEV in various tissues of HEV-challenged miniature pigs and to investigate the mechanisms underlying HEV-induced cell death in the pancreas and liver. Virological and serological analyses were performed on blood and faecal samples. Histopathology of the liver and extra-hepatic tissues was analysed. Cell death pathways and immune cell characterisation in inflammatory lesions were analysed using immunohistochemistry. The liver and pancreas displayed inflammation and cellular injury, and a large amount of HEV was observed in the lesions. The liver was infiltrated by T and natural killer cells. HEV was identified in all organs except the heart, and was associated with immune cells. Although the liver and the pancreas strongly expressed TNF-α and TRAIL, TUNEL assay results were negative. RIP3 and pMLKL were expressed in the pancreas. RIP3, but not pMLKL, was expressed in the liver. Pancreatitis induced in HEV-infected miniature pigs is associated with necroptosis.