Understanding functional and interactive changes at the single-cell level is essential for deciphering the pathogenic mechanisms of infectious diseases. However, single-cell RNA sequencing often fails to preserve spatial information and may also result in cell loss during the preparation of single-cell suspensions, limiting a comprehensive understanding of pathological changes. Spatial transcriptomics addresses these limitations by enabling in situ capture of both host and microbial transcripts. Although the application of spatial transcriptomics in infectious diseases remains limited, fully leveraging its compatibility for tailored optimization and combining it with complementary technologies will provide a powerful toolkit for unraveling pathogen–host interactions. By integrating Stereo-seq, a high-resolution spatial transcriptomics technology, with single-cell RNA sequencing, we characterized the host immune dynamics of multiple infectious diseases, including Japanese encephalitis (JE) and alveolar echinococcosis (AE). In acute JE, our analysis uncovered vasculature-centered cellular interactions, particularly between Ly6c2⁺ monocytes and Ackr1⁺ endothelial cells, that drive neuroinflammation and cell death. In chronic AE, we generated a detailed map of immune cell infiltration around infection foci, revealing the dynamic involvement of neutrophils, macrophages, and fibroblasts in the host immune response shift from "active killing" to "negative segregation" during disease progression. Together, our studies establish a spatial transcriptomics framework to identify cell-type-specific drivers, intercellular networks, and tissue remodeling mechanisms—thereby enabling rational discovery of diagnostic and immunomodulatory targets for both acute and chronic infectious diseases.