Polysaccharides are one of the main active substances in Ganoderma atrum (G. atrum). The purpose of this study was to explore the protective effect of a G. atrum polysaccharide (PSG-1) on DSS-induced colitis and the underlying mechanism. The results showed that PSG-1 could maintain the integrity of the intestinal structure by promoting the expression of goblet cells and levels of tight junction proteins in the colon of DSS-induced colitis mice. Furthermore, PSG-1 relieved the inhibition of Bcl-2 and the overexpression of caspase-3 and caspase-9 caused by DSS. Simultaneously, PSG-1 restored the expression of Atg5, Atg7 and beclin-1 and inhibited the p-akt and p-mTOR levels, suggesting that PSG-1 promoted autophagy via the Akt/mTOR pathway. Moreover, PSG-1 inhibited the content of DCs in the colon and modulated the expression of IL-10 in DCs. In conclusion, PSG-1 alleviated DSS-induced ulcerative colitis by protecting the apoptosis/autophagy-regulated physical barrier and the DC-related immune barrier.