Epigenetic histone modifications are considered as a promising avenue for cancer preventive and therapeutic strategies. The purpose of this study was to evaluate the antiproliferative and histone deacetylase (HDAC) inhibitory activity of selected peanut phenolics, including p-coumaric acid, ferulic acid, sinapinic acid and resveratrol, in MCF-7 and HeLa cells. The cytotoxic and HDAC inhibitory activities were assessed by MTT assays, flow cytometric analyses of cell cycle arrest and apoptosis induction, and western blotting. The results showed that all four phenolics inhibited proliferation of both MCF-7 and HeLa cells in a dose-dependent manner. Among the phenolics tested, resveratrol was the most effective in inhibiting growth of cancer cells. Treatment with all phenolics resulted in histone H3 hyperacetylation in both cell lines, indicating potential for HDAC inhibition. These phenolics induced apoptosis in both MCF-7 and HeLa cells in a concentration-dependent manner. Moreover, all phenolics induced G0/G1-phase arrest of the cell cycle in MCF-7 cells while p-coumaric and ferulic acids caused S-phase arrest in HeLa cells. Exposure to p-coumaric acid increased p53 and p21 expression but decreased CDK4 levels in both cell types, which could result in the observed G0/G1 arrest. Moreover, inhibition of ERK1/2 phosphorylation by ferulic acid and resveratrol contributed to cell growth inhibition. Peanut phenolics appear to influence the extent of histone acetylation in MCF-7 and HeLa cells, and this activity modulates multiple pathways that are implicated in cancer prevention.