Monascus-fermented products offer valuable therapeutic benefits and have been extensively used in East Asia. However, the polysaccharide obtained from Monascus-fermented products has never been investigated. This study evaluated the effects of dioscorea polysaccharide (DPS) and red mold dioscorea polysaccharide (RMDPS) on differentiation of leukemic THP-1 cells. DPS and RMDPS inhibited THP-1 cells proliferation in dose- and time-dependent manners. The differentiation induction (macrophage-like cells) was observed when THP-1 cells were treated with DPS and RMDPS for 5 days. Superoxide anion production, phagocytic capacity, and cytokine secretion confirmed activity for differentiating THP-1 cells. Results indicated that RMDPS elevated reactive oxygen species production and immune activity, including phagocytosis, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) productions in THP-1 cells, which was greater than that seen with DPS. These results may be attributed to Monascus-fermentation altering the carbohydrate components and polysaccharide structure. RMDPS may serve as a novel material and functional ingredient to exert anticancer capacity.