Objective To study the role and molecular mechanism of perilla seed oil extract (PSO) in reducing arterial plaque formation and providing cardioprotection in ApoE ^{-/ -} mice. Methods Three-month-old ApoE ^{-/ -} mice were randomly divided into ApoE ^{-/ -}(no drug treatment), low-dose PSO, high-dose PSO and atorvastatin groups. B6 mice of the same age were used as controls (WT group); they were fed a regular diet. After 8 weeks of treatment, biochemical tests, H&E staining, echocardiography, qPCR, ATP detection and Pro-Q Diamond staining were performed. Results Compared with the WT group, ApoE ^{-/ -} mice showed abnormal cardiac structure and function. After PSO treatment, the plaque area was reduced, and cardiac structure and function improved. mRNA expression of ANP, BNP and β-MHC was downregulated, mRNA expression of PPARα and PGC-1α was up-regulated, and the intracellular content of ATP and the phosphorylation level of TnI were increased. Conclusions PSO inhibits arterial plaque formation and maintains normal cardiac structure and function in ApoE ^{-/ -} mice. It may regulate the PPARα/ PCG-1α/ NRF-1 axis to increase ATP and myofilament phosphorylation, improve energy metabolism, and exert cardioprotective action.