This study aimed to investigate the relationship between fat deposition and endoplasmic reticulum stress of blunt snout bream through changing dietary lipid levels and adding lipolytic agents. The results showed that high fat diet (HFD) remarkably increased VSI, IPF, whole‐body lipid, tissue lipid contents, plasma levels of LDL‐C, TC and TG contents, cytosolic cytochrome c activity and Ca2+ content and the transcriptions of GRP78, IRE1, XBP1s and SREBP1, whereas the opposite was true for plasma HDL‐C content, SDH and Na+, K+‐ATPase activities in the mitochondria, Ca2+‐ATPase activity in the ER and the transcriptions of XBP1u, PPARα and CPT I. In addition, simvastatin supplementation remarkably decreased VSI, tissue lipid contents, plasma LDL‐C and TC levels, cytosolic cytochrome c activity and Ca2+ content and the transcriptions of GRP78, IRE1, XBP1s and SREBP1, while the opposite was true for plasma HDL‐C level, Ca2+‐ATPase activity and the transcriptions of XBP1u, PPARα and CPT I. Furthermore, the histological results showed that large lipid droplets and ultrastructural impairments of the mitochondria, nucleus and ER were present in hepatocytes of fish fed the HFD, while simvastatin supplementation had the potential to alleviate these damages. Taken together, these results indicated that there was an interaction between lipid deposition and endoplasmic reticulum stress induced by HFD.