The fruiting body of Auricularia auricula-judae has received attention in folk medicine due to its possible medicinal values. Therefore, this study evaluated the immunomodulatory effects of the hot aqueous extract (AAAJ) and the β-D-glucan-rich polysaccharide fraction of A. auricula-judae (BGPA) on specific and nonspecific humoral and cell mediated immune responses in immunocompetent and immunosuppressed mice. Oral supplementation with AAAJ or BGPA (100, 200, or 400 mg/kg) produced significantly high titers of total OVA specific or TT specific IgG1 and IgG2a compared with the levels in untreated control. Oral administration of AAAJ or BGPA (100, 200, or 400 mg/kg) evoked a significant increase in carbon clearance at all doses, indicating stimulation of the reticuloendothelial system, and potentiated the delayed-type hypersensitivity reaction induced by sheep red blood cells (SRBC) compared with the untreated mice. Total lymphocyte count, neutrophil count, and lymphocytes count increased significantly (P < 0.05) at all doses, following acute administration of AAAJ or BGPA (100, 200, or 400 mg/kg), showing increased protection toward cyclophosphamide induced myelosuppression compared with the untreated negative control group. In the hemolytic complement assay, AAAJ and BGPA at all doses significantly (P < 0.05) inhibited the hemolytic activity of the complement proteins on the sensitized SRBC. The present study reveals that the extract holds promise as an immunomodulatory agent and strengthens the rationale for its use in traditional medicine.