Aim To observe the effects of flavin adenine dinucleotide (FAD) on cardiac hypertrophy and cardiac fibrosis in spontaneously hypertensive rats (SHR), and to explore the mechanism of FAD on preventing and treating cardiac hypertrophy and cardiac fibrosis. Methods 12-week-old SHR and age-matched Wistar rats were selected and divided into Wistar control group, Wistar experimental group, SHR control group and SHR experimental group. After treated with FAD (1 μmol/(kg·d)) in the tail vein for 10 weeks, the sysbolic blood pressure and heart rate of the rats were detected by non-invasive blood pressure measuring instrument. Cardiac hypertrophy and cardiac fibrosis were observed by echocardiography and histology. The protein expression levels of SCAD (short-chain acyl-CoA dehydrogenase), Collagen Ⅰ, Collagen Ⅲ and α-SMA were detected by Western blot. Immunofluorescence single-label method was used to further verify the protein expression level of SCAD. The mRNA expression levels of SCAD, ANF, BNP, Collagen Ⅰ, Collagen Ⅲ and α-SMA were detected by quantitative PCR. SCAD enzyme activity, content of ATP, free fatty acids, brain natriuretic peptide (BNP) and reactive oxygen were detected. Results Systolic blood pressure and heart rate in SHR were significantly decreased after FAD treatment. Cardiac hypertrophy and cardiac fibrosis were significantly improved. SCAD mRNA, protein expression, enzyme activity and ATP content in the cardiac muscle of SHR were significantly increased. The levels of free fatty acids and reactive oxygen were significantly reduced(P＜0.05). ConclusionFAD may inhibit cardiac hypertrophy and cardiac fibrosis in SHR through activating SCAD, improving cardiac energy metabolism and reducing oxidative stress.