CTCLs represent a rare form of non-Hodgkin's lymphomas characterized by an accumulation of malignant CD4 T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with HDAC-1/8 and subsequently was deacetylated to lose its function in CTCL-cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on the p53 status. However, recent studies have shown that HDAC inhibitors could induce a wide variety of drug-resistant characteristic in cancer cells by regulating ABC transporters. Moreover, we discovered that Baicalein, a natural product, exhibited inhibitory effect on HDAC-1/8. Though the inhibition of HDAC-1 was mild, Baicalein could induce the degradation of HDAC-1 via ubiquitin proteasome pathway, thereby markedly up-regulating the acetylation of Histone H3 without promoting ABC transporter genes expression. In terms of the mechanism, Baicalein showed a better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC-1/8 and p53 in T-cell lymphoma cells, and provides a potential and safe natural HDAC inhibitor for the treatment of CTCLs.