CD47 is a widely and moderately expressed glycoprotein on the surface of all healthy cells. Its expression became an interesting research area when cancer cells were known to have an increased CD47 expression and these findings were believed to be a cellular mechanism to evade being phagocytosed by macrophages. In addition to overexpression of CD47 by cancer cells, recent studies reveal that CD47 expression on poxviruses contributes to the virulence factor by decreasing both macrophage and T cell activation. We investigated the expression and upregulation of CD47 during LCMV, Friend virus, VSV, HCV, HIV, and bacterial infections. We further determined the mechanism of CD47 upregulation and as an inhibitory molecule, we blocked the CD47 using the anti-CD47 antibody and evaluated the immune response and virus control in LCMV, VSV and HIV infection. Our findings from different mode of infections unanimously indicated an upregulation of CD47. The underlying mechanism for the CD47 upregulation is believed to be a general Toll Like Receptor activation, but cytokines such as IFNa, CXCL10 and TNFa were found to be important. We observed that the CD47 blockade significantly enhance not only innate immune response, as indicated by increased activation of macrophages, but also enhances the activation of DCs to induce better expansion of T cells in vivo and in vitro and faster LCMV clearance during acute infection. We further employed the antibody treatment in a distinct human virus model, the HIV in humanized mice. Our results show a similar pattern as that of the LCMV infection. The treatment with anti-CD47 antibody shows a reduced HIV antigen, and interestingly restores both the CD4 and CD8 T cell counts to a level comparable to healthy mice. Similar to LCMV and HIV, anti-CD47 antibody treatment shows an increased VSV-neutralizing antibody response and better survival rate of mice infected with lethal dose of VSV. Our findings indicate that CD47 acts as a checkpoint molecule that not only keeps innate immune responses in check, but also has downstream effects on the activation of adaptive immune responses during infection. In conclusion, our study was novel in the infectious disease realm. With the observed broad applicability of the anti-CD47 antibody and its mechanisms of action, it could be applicable to non-resolving acute and persistent infections associated with Epstein-Barr virus, shingles, HPV, hepatitis B, and Herpes simplex virus 2 and could be amenable to therapy for infectious diseases.