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In the light of important detrimental role of aberrant histone deacetylases (HDAC) production during various clinical complications, development of therapeutically effective and specific inhibitors of HDAC is critically important. This study deals with the screening for HDAC inhibitors from marine Actinomycetes. The isolation of Actinomycetes from 22 sediment samples along the Southern Coast of India yielded 186 strains including Streptomyces, Nocardipsis, evaluated for HDAC inhibition using HeLa cells. Among the 186 isolates, 10 strains have shown moderate to strong inhibition. The maximum inhibition (61%) was seen with strain VITKSM06 and least inhibition (31%) was seen with strain VITSJT03. The MTT cell proliferation assay using HeLa cell line showed significant cytotoxicity with an IC50 of 5·9 μg ml−1 by VITKSM06-derived metabolite and 26·2 μg ml−1 by VITSJT03. The compound treated HeLa cells displayed an altered morphology and condensed chromatin which may be due to HDAC inhibition. Based on the phylogenetic analysis, the potential strains were identified as Nocardiopsis sp VITKSM06, Streptomyces sp VITAKS1 and Streptomyces sp VITRSM02. This study reveals the importance of screening marine Actinomycetes for the discovery of potential novel HDAC inhibitors of therapeutic importance.Significance and Impact of the Study: Histone deacetylases (HDAC) are epigenetic enzymes that regulate the deacetylation in lysine group on a histone, and thus regulate the gene expression. The HDAC inhibitors are reported to promote apoptosis on tumour cells, thus become clinically important drug target. Several studies have addressed the identification of putative HDAC inhibitors as therapeutic agents for cancer and until now those cleared phase III human trials are very limited. This study attempts to investigate the chemical diversity found in marine Actinomycetes towards negative HDAC modulation, which could be used individually or in combination as anti-cancerous and other therapeutic measure.