This study aimed to compare the bioactivities of Lentinus polychrous polysaccharide extracts with Ganoderma lucidum. Three hot water-extracted polysaccharide fractions of L. polychrous (LPE), including immature fruiting bodies (im-LPE), mature fruiting bodies (ma-LPE), and mycelium (my-LPE), were analyzed for their phytochemical contents and bioactivities (e.g., anticancer, antiviral, anti-inflammatory, and immunomodulatory effects) compared with G. lucidum extract (GLE). Although GLE had the highest total phenolic and protein contents and lower carbohydrate content than LPE, im-LPE showed strong inhibition on HepG2 cell proliferation as did GLE. GLE and LPE showed antiviral effects on herpes simplex virus-1 and the relative antiproliferative activity was from im-LPE > my-LPE > ma-LPE. However, im-LPE showed the best protective activity on the viral attachment step with some virucidal effects. Moreover, all LPE showed selective and stronger inhibitory effects on LPS-induced RAW264.7 macrophages than those of GLE on genetic expression. Considering the 50% inhibitory concentration values, my-LPE possessed the strongest inhibitory activity on the expression of cyclooxygenase-2 and inducible nitric oxide synthase. However, ma-LPE had the strongest inhibitory effects on interleukin-1β and tumor necrosis factor-α gene expression. The extracts increased splenocyte proliferation under mycohaemagglutinin induction with a relative order of my-LPE > GLE > ma-LPE = im-LPE. In conclusion, LPE showed positive effects and stronger activity than G. lucidum. L. polychrous may have potential for use as an ingredient in functional foods.