C646 is a newly discovered competitive p300/CREB-binding protein-specific inhibitor. Previous studies have shown its potential antitumor activity, but the immunomodulatory function of C646 remains largely unknown. In this study, we investigated the effects of C646 in cytokine expression and antibacterial activity in mouse macrophages. Results showed that C646 significantly reduced LPS-induced pro-inflammatory cytokines, which relied on suppression of JNK, ERK1/2, and NF-κB p65 signaling pathways. In addition, the inhibitory effects were not associated with modulating the expression of CD14/TLR4/MD2 complex or antagonizing its binding ability to LPS. Furthermore, C646 also down-regulated the levels of FcγR III/II and CR3 on macrophage, impaired the phagocytic ability against E. coli, and blocked phagosome-lysosome fusion. Consistent with this, C646 inhibited macrophage-associated bactericidal ability. Collectively, these data indicated that C646 exhibited potent immunomodulatory effects on macrophage both in the production of pro-inflammatory cytokines and bacterial phagocytosis.