Avian influenza viruses (AIVs) cause significant economic losses to the poultry industry and pose a persistent threat to public health due to their capacity for cross-species infection of mammals and humans. From May 2021 to April 2025, six severe human cases of H10N3 infection were successively reported across Jiangsu, Zhejiang, Yunnan, Guangxi, and Shaanxi provinces, China, with patient ages ranging from 23 to 70 years. These cases exhibited a sporadic pattern, characterized by a wide geographical distribution and long intervals between occurrences. The H10N3 strains originated from poultry, and all affected individuals had a history of exposure to live poultry. There is no evidence that H10N3 have acquired the ability for sustained human-to-human transmission. H10N3 viruses were found to be circulating at a low prevalence in poultry in Eastern China, with an overall isolation rate of 0.41%. While chickens were identified as the primary host, these viruses were also detectable in waterfowl. However, it is noteworthy that systematic virological studies have demonstrated that H10N3 viruses have gained the ability to infect and adapt to mammalian in hosts. This elevates the concern for their potential to continue causing sporadic human infections and even pose a pandemic risk in the future. In this communication, we focus on the origins of H10N3 and the molecular mechanisms underlying its cross-species infection of mammals.