Objective To investigate the effect of conditional knockout of inhibitory receptor T-cell immunoreceptor immunoglobulin and tyrosine-based inhibitory motif domain (tigit) in natural killer (NK) cells on disease progression in a model of schistosomiasis liver fibrosis and unravel the underlying mechanisms. Methods Four mice with tigit conditional knockout NK cells were used as the experimental group, and four wild-type mice in the same litter served as controls. All mice were percutaneously infected with Schistosoma japonicum cercariae (20 ± 2 per mouse), and mouse liver tissues were sampled 6 weeks post infection. The morphological structure of egg granulomas, degree of inflammatory cell infiltration, and collagen fiber deposition were observed using hematoxylin and eosin (HE) staining and Masson’s trichrome staining, and the degree of liver fibrosis was assessed using immunohistochemical staining of α smooth muscle actin (α-SMA). The percentage of positively stained area was calculated using the software ImageJ. The relative mRNA expression of alpha smooth actin (acta2), Ⅰ-collagen (I-c) and tigit was quantified with a reverse transcription quantitative Real-time PCR (RT-qPCR) assay. Total RNA extracted from mouse liver tissues was subjected to transcriptome sequencing to identify differentially expressed genes, followed by Gene Ontology (GO) functional enrichment analysis. All statistical analyses were performed using the software GraphPad Prism 9, and differences of means were tested for statistical significance with independent samples t test. Results HE staining revealed smaller areas of egg granulomas and milder inflammatory cell infiltration in the experimental group relative to the control group. Masson’s trichrome staining showed reduced collagen deposition that was confined to localized areas and presented as slender fibrous strands in mouse liver tissues in the experimental group, and deposition of extensive blue collagen fibers in mouse liver tissues in the control group, producing obvious fibrous encapsulation around egg granulomas. The score for collagen deposition was significantly lower in the experimental group (8.07 ± 0.52 points) than in the control group (26.07 ± 1.54 points) (t = 19.22, P < 0.01). Immunohistochemical staining for α-SMA revealed a marked decrease in positive α-SMA expression and staining intensity in mouse liver tissues in the experimental group, whereas widespread positive α-SMA expression was detected in mouse liver tissues in the control group, which was mainly found around activated hepatic stellate cells around granulomas and in the perisinusoidal spaces. Semi-quantitative analysis revealed a lower percentage of α-SMA positive areas in the experimental group (3.39 ± 1.25) than in the control group (8.60 ± 2.47) (t = 5.92, P < 0.01). RT-qPCR assay quantified lower relative mRNA expression of the fibrosis-related genes acta2 [(0.87 ± 0.06) vs. (1.40 ± 0.03); t = 14.93, P < 0.01], I-c [(0.88 ± 0.03) vs. (1.2 ± 0.02); t = 14.99, P < 0.01], and tigit [(1.67 ± 0.15) vs. (1.03 ± 0.11); t = 6.216, P < 0.01] in the experimental group than in the control group. Transcriptome sequencing identified 431 differentially expressed genes (365 up-regulated and 66 down-regulated genes), and GO enrichment analysis indicated that the up-regulated genes were significantly enriched in immune response-related pathways, including pathways of NK cell degranulation, negative regulation of hepatic stellate cell activation, and neutrophil chemotaxis and migration. Conclusion Conditional knockout of tigit in NK cells may alleviate schistosomiasis liver fibrosis in mice by restoring NK cell functions and inhibiting hepatic stellate cell activation, and affect the neutrophil pathway, suggesting that TIGIT has a complex regulatory role in the liver immune microenvironment.