Histone deacetylases (HDACs) repress transcription by deacetylating acetyllysines on specific histone tails. HDAC3 is implicated in neurodegenerative diseases, certain leukemias, and even in disrupting HIV‐1 latency. A recent crystal structure of HDAC3 in complex with the deacetylase‐activating domain (DAD) of its corepressor complex revealed an inositol tetraphosphate (IP4) molecule at the protein–protein interface. IP4 was shown to play an important, yet mechanistically ambiguous, role in the activity of HDAC3. The goal of this article is to explore the conformational ensemble of HDAC3 in its inactive apo state and in the presence of each or both of DAD and IP4. Using triplicate, 100 ns molecular dynamic simulations, we study the apo, ternary, and intermediate DAD‐bound or IP4‐bound HDAC3 states. We find that a population‐shift effect is induced by the presence of each corepressor, and is most notable in the presence of both. Our results offer new insights into the change in dynamics necessary for the activation of HDAC3 and highlight the roles of IP4 and DAD in this process.