Newly emerging or "re-emerging" influenza viruses have been regarded as a huge global threat to human public health. However, there are few reports of human deaths caused by newly emerging influenza viruses derived from pigs and poultry. Here, we described the clinical and virological features of a fatal encephalitis caused by a novel H3N2 reassortant virus generated from swine H3N2 and human H7N9 viruses. A 7-year-old boy was diagnosed with acute encephalitis in Yixing, China, in August 2022. Chest computed tomography (CT) showed mild pneumonia. Brain CT indicated acute encephalitis companied brain parenchyma swelling. Haematological examinations revealed a markedly elevation of lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, creatine kinase and cytokines. Pathogenic analysis confirmed that a novel H3N2 virus (A/Yixing/805/2022, YX805) was responsible for this case. Phylogenetic analysis showed that the surface protein-coding genes were originated from swine-origin H3N2 viruses, whereas the internal protein-coding genes were derived from human-origin H7N9 viruses. This virus triggers stronger cytokines storm than these genetically related H7N9 viruses and has a natural resistance to neuraminidase inhibitors. The YX805 virus is highly pathogenic to mice. Our study highlights the urgent need to enhance epidemiological surveys for reassortment events between swine and avian influenza virus by full genome sequencing.