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Ecological immunology involves the study of the immune function of wildlife, which is seldom compared with that of model animals. Here, we evaluated and compared the level of the innate immune response in the plateau zokor (Eospalax baileyi), an indigenous underground rodent from the Tibetan Plateau, with that in the bamboo rat (Rhizomys pruinosus) and Sprague‐Dawley (SD) rat (Rattus norvegicus). The spleen was observed by ordinary light and transmission electron microscopy, and the spleen index was calculated. After liposaccharide (LPS) challenge, the expression of Toll‐like receptor 2 (TLR2), TLR4, and hypoxia‐inducible factor 1α (HIF‐1α) in the spleen was detected by Western blot analysis and immunofluorescence. The expression of nuclear factor‐κB1 (NF‐κB1) and mitogen‐activated protein kinase 14 (MAPK14) in the spleen was detected by real‐time quantitative polymerase chain reaction, and the levels of interleukin 6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and interferon‐β (IFN‐β) in the spleen were detected by enzyme‐linked immunoassay. The spleen index of the plateau zokor was lower than that of the bamboo rat and SD rat. The expression of TLR4, NF‐κB1, and MAPK14 and the levels of IL‐6 and TNF‐α in the spleen of the plateau zokor were lower than those of the bamboo rat and SD rat, while the expression of TLR2 and HIF‐1α and the level of IFN‐β were higher than those of the bamboo rat and SD rat. We speculate that suppression of the TLR4 signaling pathway in the plateau zokor is an adaptation to hypoxic tunnels that decreases antigenic risk and maintains immune homeostasis. Moreover, the spleen of the plateau zokor is reduced in size, reducing the innate immunity investment in the spleen. We also noted that high levels of HIF‐1α in the spleen of the plateau zokor suppressed crosstalk between HIF‐1α and TLR4, promoting the innate immune response.