Emerging studies have demonstrated that phagocytosis checkpoints, which promote tumor-mediated immune evasion, are potential targets for cancer immunotherapy. In this study, the TCGA colorectal cancer (CRC) dataset and our RNA sequencing dataset suggested that SLAMF8 expression is significantly positively correlated with the expression levels of multiple phagocytosis checkpoint molecules. In vitro, we confirmed that SLAMF8 significantly regulated the phagocytosis of mouse CRC cells. RNA sequencing revealed that the expression of genes that promote Fc receptor (FcR)-mediated phagocytosis, such as FCGR1, FCGR3, FCGR2b, FCGR4, and ITGAM, was significantly upregulated after SLAMF8 knockdown. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results suggested that the significantly enriched signaling pathways after SLAMF8 knockdown or overexpression included the PI3K-Akt signaling pathway. The protein expression levels of p-PI3K and p-Akt were significantly increased after SLAMF8 knockdown. When PI3K inhibitors and Fc blockers were added after SLAMF8 knockdown, mouse macrophage phagocytosis, and FcR expression decreased. Our results suggest that SLAMF8 may impair FcR-mediated phagocytosis through the PI3K-Akt signaling pathway and negatively regulate the antitumor immune response.