Objective To investigate the effects of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a second messenger molecule, on liver egg granulomas and fibrosis in Schistosoma japonicum-infected mice and to preliminarily clarify its regulatory mechanism. Methods C57BL/6 mice were randomly divided into cGAMP-treated group (8 mice), infected control group (28 mice), and infected cGAMP-treated group (28 mice). For the cGAMP-treated group, cGAMP (2 μg, 100 μl) was injected via the tail vein, while the infected control group and the infected cGAMP-treated group were injected with PBS (100 μl) and cGAMP (2 μg, 100 μl) via the tail vein once a week, respectively, after being infected with S. japonicum cercariae [(20 ± 2)/mouse] via abdominal skin patch. From each group, 8 mice received 10 ingections to observe survivl state after each injection. After 7 weeks, mice orbital blood samples from infected control group and infected cGAMP-treated group (each 5) were collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by ELISA. The liver tissues sections were prepared and stained with hematoxylin eosin (HE) and Masson to estimate the area of individual egg granuloma and fibrosis, and count the number of eggs in the liver tissues. Mice liver tissues were collected from infected control group and infected cGAMP-treated group (15 each), on 0, 4, and 7 weeks post-infection, for extraction of total RNA, which was used for performing real time fluorescent quantitative PCR (qRT-PCR) to examine the expression level of IFN-β-encoding gene Ifnb1; the mice orbital blood was collected to detect the serum β-interferon (IFN-β) level by ELISA. GraphPad Prism 8.0.2 software was used for statistical analysis, and t-test was used for comparison between the two groups. Results There were no deaths in the cGAMP-treated group, and 10 weeks after infection, 2 mice died in the infected control group and 5 mice died in the infected cGAMP-treated group, with statistically significant differences between the two groups (χ² = 7.55, P < 0.01). The number of eggs in the liver of mice from the infected control group and the infected cGAMP-treated group was 50 600 ± 15 473 and 53 400 ± 16 273, respectively, with no statistically significant difference (t = 0.28, P > 0.05). HE staining showed significant liver histopathological damage in both the infected control and infected cGAMP-treated groups, with proportions of (35.32 ± (15.09)% and (64.98 ± 13.91)% (t = 3.23, P < 0.05), respectively. The area of liver egg granulomas was (0.57 ± 0.45) mm² and (1.17 ± 0.74) mm² in the infected control and infected cGAMP-treated groups, respectively (t = 2.95, P < 0.01). Masson staining showed that liver fibrosis occurred in both the infected control and infected cGAMP-treated mice, with proportions of (24.50 ± 6.39)% and (39.02 ± 6.79)%, respectively (t = 3.48, P < 0.01). At 4 and 7 weeks post-infection, the expression levels of Ifnb1 mRNA in liver tissues of mice from infected cGAMP-treated group were 16.58 ± 6.71 and 10.52 ± 2.88, respectively, which were upregulated compared with 9.280 ± 4.50 and 6.62 ± 1.58 in the infected control group (t = 2.95, 2.18, P < 0.05). The serum IFN-β levels in the infected cGAMP-treated group were (1 206.45 ± 211.87) pg/ml and (960.62 ± 151.33) pg/ml, respectively, which were upregulated compared to (845.12 ± 284.11) pg/ml and (685.20 ± 143.88) pg/ml in the infected control group (t = 2.28, 2.95, P < 0.05). ALT was (394.80 ± 72.82) U/L and (627.20 ± 93.58) U/L (t = 4.38, P < 0.01) and AST was (605.00 ± 148.90) U/L and (871.80 ± 138.10) U/L (t = 2.94, P < 0.05) in the mice of infected control and infected cGAMP-treated groups, respectively. Conclusion cGAMP promots liver egg granuloma formation and fibrosis in mice infected with S. japonicum, indicative of exerting the promotive effect through inducing type Ⅰ interferon immune response.