Acetylation is an important modification type of histones, which is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, the histone acetylation level of Monascus was enhanced through the exogenous addition of the HDACs inhibitor vorinostat, and the regulation effects of histone acetylation on cell growth and secondary metabolism were evaluated. The results demonstrated that the augmentation of histone acetylation level could slightly facilitate sugar consumption, increase biomass weight, and significantly induce noticeable morphological alterations. Furthermore, in the presence of 80 μmol/L vorinostat concentration, there was a significant reduction observed in both extracellular and intracellular Monascus pigments, citrinin productions, with decreases of 35.46%, 63.90%, and 98.33% respectively. RT-qPCR results showed that adding vorinostat resulted in the up-regulation of HAT genes and down-regulation of HDAC genes. Additionally, transcriptome analysis revealed that glycolysis, tricarboxylic acid cycle, fatty acid metabolism, cell membrane anchor-protein related genes, and biosynthetic pathways involved in ergosterol and chitin synthesis were upregulated. Conversely, the electron transport chain and genetic clusters associated with Monascus pigments and citrinin synthesis were down-regulated. These findings underscore the pivotal role of histone acetylation in regulating the cell growth and secondary metabolism of M. purpureus and extend novel perspectives on the potential applications of clinical compounds derived from this process.