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Background: Pathogens can impact host RNA modification machinery to establish a favorable cellular environment for their replication. In the present study, we investigated the effect of Toxoplasma gondii infection on host RNA modification profiles and explored how these modifications may influence the host-parasite interaction. Methodology/principal findings: We analyzed the modification levels of ∼ 80 nt tRNA and 17–50 nt sncRNAs in mouse liver, spleen, and serum using liquid chromatography and tandem mass spectrometry analysis. The results revealed alterations in RNA modification profiles, particularly during acute infection. The liver exhibited more differentially abundant RNA modifications than the spleen. RNA modification levels in serum were mostly downregulated during acute infection compared to control mice. Correlations were detected between different RNA modifications in the liver and spleen during infection and between several RNA modifications and many cytokines. Alterations in RNA modifications affected tRNA stability and protein translation. Conclusions/significance: These findings provide new insight into the role of RNA modifications in mediating the murine host response to T. gondii infection. Author summary: The dynamic landscape of host tissue RNA modifications and its possible association with the immune response to Toxoplasma gondii infection are poorly understood. Here, we analyzed the patterns of 20 RNA modification types in the liver, spleen and serum of mice infected by T. gondii. We characterized the levels of modifications of total RNA, ∼ 80 nt tRNA and 17–50 nt sncRNAs using LC-MS/MS. Differentially abundant RNA modifications were more frequent during acute infection compared to chronic infection and were more pronounced in the liver than in the spleen. Multiple tRNA modifications were co-regulated during chronic infection. Several RNA modifications showed significant correlation with serum cytokines, highlighting the role of RNA modifications in the immune response to T. gondii infection. Alterations of RNA modifications affected tRNA stability and the translation of eukaryotic initiation factor 4A/E. These findings provide new insight into the role of RNA modifications in the pathogenesis of and immune response to T. gondii infection. [ABSTRACT FROM AUTHOR]