Swine influenza virus causes a substantial disease burden to swine populations worldwide and poses an imminent threat to the swine industry and humans. Given its importance, we characterized two swine influenza viruses isolated from Shandong, China. The homology and phylogenetic analyses showed that all eight gene segments of A/swine/Shandong/AV1522/2011(H1N1) were closely related to A/Maryland/12/1991(H1N1) circulating in North America. The HA, NA, M, and NS genes of the isolate were also confirmed to have a high homology to A/swine/Hubei/02/2008(H1N1) which appeared in China in 2008, and the virus was clustered into the classical swine lineage. The gene segments of A/swine/Shandong/AV1523/2011(H1N1) were highly homologous to the early human H1N1 and H2N2 influenza viruses, except for the HA gene, and the virus was a reassortant H1N1 virus containing genes from the classical swine (HA) and human (NA, PB2, PB1, PA, NP, M, and NS) lineages. Both the viruses could cause lethal infection and replicate efficiently in the lungs, brains, spleens, and kidneys of mice. Histopathological examinations showed that AV1522 and AV1523 viruses caused a spectrum of marked pneumonia and meningoencephalitis according to the duration of infection, demonstrating a progression of respiratory disease and neurological disease over the course of infection that ultimately resulted in lethality for the infected mice. The changes in the pathogenicity of swine influenza viruses to mammals, accompanied with the continuous reassortment and evolution of the viruses, highlights the importance of ongoing epidemiological investigation.