Senegalia macrostachya (Reichenb. ex DC.) Kyal. & Boatwr seed (SMS) is a wild legume used as food and medicine in many African countries. In the current study, a novel polysaccharide (SMSP2) was extracted from SMS using hot water and purified with DEAE-52 cellulose. Its structure was characterized, and the immunomodulatory activity and possible molecular mechanism in murine macrophage RAW264.7 were explored. The results revealed that SMSP2 was a uronic acid-rich polysaccharide (51.6%, w/w) with a molecular weight of 52.07 kDa. The neutral sugars were mainly arabinose, xylose, mannose, and galactose at a molar ratio of 1.00 : 0.84 : 0.90 : 0.07. Interestingly, SMSP2 treatment markedly promoted macrophage proliferation and phagocytosis and induced the expression of inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10. SMSP2-induced macrophage stimulation occurs through the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, macrophage surface complement receptor 3 (CR3) might play an important role in SMSP2-induced macrophage activation. This study revealed that SMSP2 is a potent immunomodulator, which could be used as a functional food and a pharmaceutical adjuvant in treating immune-compromising diseases.