Studies on effects of cranberry products in animals, especially in chickens, are very scarce or even lacking. This study investigated the immunomodulatory effect of high molecular weight non-dialyzable materials (NDMs) of cranberry extract. The in vitro antioxidant and anti-inflammatory activities were investigated. The ability of NDMs (0, 1, 2, or 4 mg/mL) to enhance phagocytic activities was also evaluated using chicken heterophils (CHEs) against Staphylococcus aureus. Furthermore, a broiler model was used to determine the effect of NDMs on the humoral immune response. Seven-d-old chicks were vaccinated with the infectious bursal disease virus (IBDV) vaccine S-706, and treated orally with 0, 2, 4, or 8 mg/mL/bird NDMs for five consecutive days. Serum immunoglobulin level (Ig), and antibody concentration against IBDV, infectious bronchitis virus (IBV), Newcastle disease virus (NDV), and avian reovirus (ARV) were measured weekly by enzyme-linked immunosorbent assay (ELISA). NDMs showed >five-fold higher antioxidant activity (oxygen radical absorbance capacity = 222.7 mg trolox/g) than the commercial raw cranberry juice from which it derived (oxygen radical absorbance capacity = 39.6 mg trolox/g). Likewise, NDMs demonstrated anti-inflammatory activities comparable to Naproxen but better than those of Ibuprofen. The susceptibility of S. aureus to phagocytosis by CHEs increased significantly (P < 0.05) at 4 mg/mL NDMs in the medium. While no intracellular bacteria were counted in CHEs after phagocytosis in the presence of 2 and 4 mg/mL NDMs, 1 mg/mL NDMs demonstrated a significant (P < 0.05) intracellular killing activity in CHEs against S. aureus compared to the untreated CHEs. Results from the in vivo studies indicated that birds receiving 2 and 4 mg/mL/bird NDMs had a higher serum IgM level (P < 0.05), and their antibody titers against IBDV tended to increase with NDMs administration (P = 0.06) on d 35. These results suggest that NDMs enhances bacterial susceptibility to immuno-defense mechanisms, and may be useful as immunomodulators against infections.