The avian influenza virus (AIV) primarily affects birds and poses an increasing concern due to its growing adaptability to other hosts, heightening zoonotic risks. The adaptability is a key factor in AIV to infect multiple non-avian species, including humans, companion animals, aquatic mammals, carnivores, and other mammals. The virus is evolving through genetic mutations and reassortments, leading to the emergence of AIV strains with enhanced virulence and adaptability in mammals. This highlights the critical need to understand the genetic factors of AIV, including mutations in polymerase proteins, surface antigens, and other regulatory proteins, as well as the dynamics of AIV-host interactions and environmental factors such as temperature, humidity, water salinity, and pH that govern the cross-species adaptability of the virus. This review provides comprehensive insights into the molecular/genetic changes AIV undergoes to adapt in mammalian hosts including bovines, swine, equines, canines, and felines. The adaptive mutations in viral polymerase proteins, such as PB2-E627K, and receptor specificity shift facilitate the virus adaptability in mammals. Since AIVs interact with specific receptors on host cells, therefore the type and distribution of receptors are crucial in determining the host range of the virus and its adaptability by facilitating attachment and entry of the virus. This review examines sialic acid receptor distribution and binding patterns in various mammalian hosts, emphasizing how the presence and structure of specific receptors influence viral interaction, adaptation, and transmission. The review concludes that the differential distribution and expression of SA receptors are vital in the mammalian adaptability and tissue tropism of viral strains. Notably, during the adaptation to mammals, AIVs show a shift in preference from α-2,3 to α-2,6 receptors. This review further emphasizes the role of ecological determinants in the adaptation of viruses to mammalian hosts. Low temperatures, high humidity, and neutral to slightly acidic pH levels enhance virus stability, facilitating its persistence in the environment and spread among susceptible hosts. Overall, AIV remains a global health threat, necessitating coordinated efforts in research, surveillance, and public health strategies.