Fibroblast growth factors (FGFs) mediate key cardiac functions from development to homeostasis and disease. The current research was to explore the effects of FGF12 in the fibrosis of cardiac function and heart failure, and whether FGF12 alleviated cardiac fibrosis via inhibition of oxidative stress. Ligation of left coronary artery in mice induced heart failure and myocardial infarction (MI). Angiotensin II (Ang II) was administered to cardiac fibroblasts (CFs). FGF12 upregulation or FGF12 transgenic (Tg) mice could improve cardiac dysfunction of MI mice, and attenuated cardiac fibrosis of heart failure induced by MI in mice. FGF12 overexpression suppressed the increases of collagen I, collagen III and fibronectin which was induced by Ang II in CFs. The oxidative stress was enhanced in the heart of MI mice and CFs treated with Ang II, and these enhances were attenuated via FGF12 overexpression. Superoxide dismutase (SOD) overexpression inhibited the enhancements of collagen I, collagen III and fibronectin in the heart of MI mice, and in the CFs treated with Ang II. Overexpression of nicotinamide adenine dinucleotide phosphate oxidases (Nox1) reversed the attenuating influences of FGF12 on the enhancements of collagen I, collagen III and fibronectin in the CFs induced by Ang II. These outcomes showed that FGF12 upregulation can improve cardiac dysfunction and heart fibrosis of heart failure. FGF12 attenuates oxidative stress to suppress the cardiac fibrosis.