Ganoderma lingzhi (reishi) (GL) is a widely used medicinal mushroom in the treatment of several diseases, including metabolic syndrome and cancer. We recently performed autodigestion of GL and found enhanced release of hypotensive peptides and immunomodulating beta-1,3-glucan. In the present study, we examined the protective effects of G. lingzhi and its autodigested product (AD-GL) against gut inflammation and endogenous sepsis induced in mice by the oral administration of indomethacin (IND). Gut inflammation was assessed by measuring the lengths of the intestines and colon, and sepsis was evaluated by the survival period. G. lingzhi and AD-GL were mixed with animal feed (2.5%) that was available ad libitum during the experimental period. The murine model was established by the repeated oral administration of IND (once a day, 5 mg/kg from day 0). On day 3, the lengths of the small intestine and colon were measured, and the average lengths of the intestines were significantly shorter in the control and G. lingzhi-administered groups than in the AD-GL-administered group. This finding suggests that AD-GL protected against gut inflammation due to IND-induced ulceration and subsequent microbial translocation. Furthermore, the median numbers of survival days in the control group, the G. lingzhi group, and the AD-GL group were 5, 6, and 11, respectively. The concentrations of the inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin-6, in the blood were significantly reduced in the mice administered AD-GL. In the in vitro cell culture, G. lingzhi and AD-GL fractions released a significantly higher concentration of TNF-α from the spleen, and the splenocytes of mice administered AD-GL hot water extract showed a greater potential to produce cytokines in response to pathogen-associated molecular patterns. These results strongly suggest the protection of the gut mucosa from inflammation, and therefore the prevention of sepsis, by the administration of AD-GL. Autodigestion appears to be a promising protocol that enhances the usefulness of G. lingzhi as a functional food.