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In human immunity, the spleen is a major organ, being central to humoral and cellular immunity. In vitro and in vivo, inflammation is regulated by ubiquitin-specific protease 8 (USP8); however, to the best of our knowledge, the effect of USP8 on spleen injury remains unknown. The present study aimed to investigate the protection offered by USP8 against spleen injury in lipopolysaccharide (LPS)-induced mice via attenuation of inflammation. A total of 119 C57BL/6J mice were placed into the following groups: Control group, saline group, LPS group, USP8 group, USP8 + LPS group and negative control (NC) + LPS group. A USP8 lentivirus was injected into mice at 1×108 TU/ml intracerebroventricularly for 7 days before LPS was administered via intraperitoneal injection at 750 µg/kg. From each group, serum and spleen samples were collected for analysis. Histological imaging was used to examine the spleen structure. Western blotting was used to detect the expression levels of proteins associated with the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling pathways. Pro-inflammatory cytokines were detected using enzyme-linked immunosorbent assays. Compared with that in the saline, control and USP8 + LPS groups, the spleen volume in the LPS group was markedly increased, and the width of the splenic cord and sinus exhibited morphological damage in the LPS group. Compared with that in the saline, control and USP8 + LPS groups, the protein expression levels of USP8 in the spleen were decreased in the LPS group. Furthermore, the production of LPS-induced pro-inflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α) was reduced in serum and spleen homogenates by USP8. Related inflammatory pathways, including the NF-κB and MAPK pathways, were downregulated in the USP8 + LPS group compared with those in the LPS group. In conclusion, the anti-inflammatory effect of USP8 on LPS-induced spleen injury may be mediated by the inhibition of MAPK and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]