<p>Host-associated microbiomes play a crucial role in various biological processes, including host physiology, health, and evolution. However, despite its importance, the oral microbiome of wild animals such as the giant panda (<i>Ailuropoda melanoleuca</i>), remains poorly studied. Here we presented the initial comprehensive metagenomic analysis of the giant panda’s oral microbiome using shotgun sequencing, generating the valuable data for this endangered species. Our study included 118 samples, comprising 28 supragingival samples (11 giant pandas and 3 Asiatic black bears (<i>Ursus thibetanus</i>), also known as a moon bear, collected by us, along with 14 human (<i>Homo sapiens</i>) samples originating from public datasets.) as well as 90 fecal samples from public databases. Our findings indicated that the oral and gut microbiomes of Ursidae were different from those of humans, both taxonomically and functionally. These results suggest that phylogenetic factors, rather than ecology, play an important role in shaping the oral and gut microbiomes (phylosymbiosis). Notably, periodontal opportunistic pathogens in humans coexisted with giant pandas, other bears and gorillas without dental issues. This suggests immune tolerance mechanisms may increase with long-term coevolution in host-microbiome, enabling pathogen coexistence without inflammatory harm. Lastly, giant pandas exhibited a high abundance of nitrate-reducing oral taxa, which may contribute to their adaptation to the environment and promoting oral health. This initial study not only enhances our understanding of host-microbiome interactions but also demonstrates the importance of metagenomic approaches in conservation biology, which could contribute to the long-term conservation of giant pandas.</p>