Southern China is considered an important source of influenza virus pandemics because of the large, diverse viral reservoirs in poultry and swine. To examine the trend in influenza A virus of swine (IAV-S), an active surveillance program has been conducted from 2013 to 2015 in Guangdong, China. The phylogenetic analyses showed that the external genes of the isolates were assigned to the Eurasian avian-like swine (EA) H1N1 and/or human-like H3N2 lineages with multiple substitutions, indicating a notable genetic shift. Moreover, the internal genes derived from different origins (PB2, PB1, PA, NP: pdm/09 (pandemic influenza virus 2009)-origin, M: pdm/09- or EA-origin, NS: North American Triple Reassortant (TR)-origin have become the dominant backbone of IAV-S in southern China. According to the origins of the eight gene segments, the isolates can be categorized into five genotypes. The results of mice experiment showed that the YJ4 (genotype 1) and DG2 (genotype 4) are the most pathogenic to mice, and the viruses are observed in kidneys and brains, indicating the systemic infection. The alterations of the IAV-S gene composition supported the continued implementation of the intensive surveillance of IAV-S and the greater attention focused on potential shifts toward transmission to humans.