Abstract Aim Immunotherapies blocking the CD 47‐ SIRP α pathway by targeting CD 47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRP α exhibits relatively restricted tissue expression, SIRP α antagonists may be better tolerated than agents targeting CD 47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies ( mA bs) against CD 47 and/or SIRP α on gastroenterological tumors in syngeneic immunocompetent mouse models. Methods We used in vitro and in vivo phagocytosis assays in C57 BL /6J (B6) mice to investigate anti‐ CD 47/ SIRP α mA b effects on Hepa1‐6 and CMT 93 originating from B6 mice. The influence of these mA bs on macrophage transmigration was also assessed. To investigate anti‐ SIRP α mA b therapy‐induced inhibitory effects on sporadic colon cancer growth, we used a CDX 2P9.5‐ NLS Cre; APC + /FLOX ( CPC ‐ APC ) mouse model. Results Systemic anti‐ SIRP α mA b administration significantly increased Hepa1‐6 and CMT 93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti‐ CD 47 mA b did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti‐ CD 47 mA b prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti‐ CD 47 mA b inhibited macrophage transmigration. Anti‐ SIRP α mA b treatment inhibited tumor progression in CPC ‐ APC mice and significantly improved overall survival. Anti‐ CD 47 mA b administration in vivo eliminated the phagocytosis‐promoting CD 47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti‐ SIRP α mA b exhibited enhanced macrophage phagocytic activity and marked anti‐tumor effects against gastroenterological malignancies. Conclusion SIRP α mA b augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors.