This study focused on the mechanism of CD47 expression mediated by histone deacetylase inhibitor (HDACi) in B-cell lymphoma. After treatment with HDACi (SAHA) of different doses for different time courses, cell surface expression of CD47 in mouse B lymphoma cell line A20 was detected by FACS. Then TRIzol was used to extract RNA from SAHA-treated mouse and human B lymphoma cell lines for determination of CD47 mRNA levels. In order to explore the underlying molecular mechanisms, we used chromatin immunoprecipitation assay to detect the binding of H3K4ac, H3K9ac and H3K27ac at the promoter region of CD47. Finally, CD47 levels were measured by FACS after combined treatment with SAHA and BRD4 inhibitor JQ1. The results showed that the levels of CD47 protein and mRNA were positively correlated with the dose of SAHA and time of treatment. Moreover, the acetylation levels of H3K4, H3K9 and H3K27 at the promoter region of CD47 were significantly increased by SAHA treatment. The combined use of SAHA and JQ1 significantly reversed the up-regulated CD47 by SAHA. Taken together, SAHA up-regulates CD47 expression through enhancement of its transcription, while inhibition of BRD4 can reverse SAHA-mediated CD47 up-regulation.