The purpose of this study is to determine the potential of piceatannol (PT) in statin resistance and tolerance related with hypercholesterolemia. We investigate the epigenetic mechanisms of proprotein convertase subtilisin/Kexin type 9 (PCSK9) expression through p300 acetyltransferase inhibition activity. HepG2 cells were used for in vitro study and exposed to statins (rosuvastatin or simvastatin) with PT in delipidated serum (DLPS) medium for cholesterol in starvation. Statin was treated the HepG2 cells with mevalonate in DLPS medium. An in vivo study was performed with hypercholesterolemia mice model. Male C57BL/6J mice were fed with a high fat diet for 16 weeks. Simvastatin and PT treatment were provided by oral gavage for 10 weeks. It is well established that PCSK9 and LDLR are the main factors of controlling the LDL cholesterol levels in hypercholesterolemia. To determine whether PT treatment changes in expression levels of LDLR and PCSK9, we measured the protein and mRNA expression of two proteins in HepG2 cells. PT significantly decreased PCSK9 expression and stabilized LDLR expression by blocking lysosomal degradation in HepG2 cells exposed with DLPS condition.