Secretory immunoglobulin A (SIgA) is a non-inflammatory antibody that shields internal body surfaces, such as in the intestine to neutralize pathogens in the lumen of the intestine. As chemotherapy seriously damages the mucosal immune system, we herein demonstrated that polysaccharide from the squid ink of Ommastrephes bartrami (OBP) activated intestinal SIgA secretion to prevent chemotherapeutic injury. Using a mouse model of chemotherapy induced intestinal injury by intraperitoneal injection of 50 mg kg(-1) cyclophosphamide, our results showed an enhanced SIgA concentration in intestinal mucosa by OBP administration and the higher production of SIgA relied on the greater expression of IgA, J chain and pIgR. Furthermore, the higher expressions of IL-6, IL-10 and TNF-α increased by OBP treatment contributed to enhanced IgA and J chain synthesis in IgA(+) plasma cells, and pIgR expression in epithelial cells. It also triggered a prompt immunoglobulin secretory pathway confirmed by enhanced UPR (unfolded protein response) effectors XBP-1s and Bip expression. Our results have important implications for the mucosal immunity enhancement effects of OBP as a functional food component for chemotherapeutic patients.