Objective To investigate the molecular mechanism of mitochondrial mitochondrial ATP-sensitive potassium channels (mitoKATP) opener in improving myocardial oxidative stress/injury in rates with coronary heart disease (CHD). Methods A total of 40 SD rats were randomly divided into 4 groups with 10 in each:control group (without modeling and intervention of diazoxide drug), sham operation group (with skin cutting but without modeling), and model group (modeling of coronary heart disease but without intervention of diazoxide) and drug group (with modeling of coronary heart disease and intervention of diazoxide at 3 mg/kg). mRNA expression of angiogenic factors[fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF)] and related proteins for each group were measured using real-time fluorescence quantitative polymerase chain reaction and Western blotting. The groups were compared in lactate dehydrogenase, mitochondrial membrane potential (MMP) and cell death rate. SPSS statistics 22.0 was used of data processing, and analysis of variance (ANOVA) or t test for comparison between groups. Results Compared with the model group, drug group had significantly lower mRNA transcription of FGF-2 [(100.21±12.33)×10³ vs (120.43±10.33)×10³ IU] and VEGF [(163.31±9.33)×10³ vs (181.33±11.13)×10³ IU] and expression of FGF-2 [(0.69±0.33) vs (1.32±0.33)], VEGF [(0.68±0.33) vs (1.20±0.13)], and lactate dehydrogenase [(49.32±3.51) vs (156.12±10.18)U/L]. Compared with the model group, the cell death rate in the drug group decreased [(30.32±3.48)% vs (66.12±3.23)%], but the fluorescence intensity increased [(780.12±9.20) vs (220.24 ±6.15)] (P<0.05). Conclusion mitoKATP channel opener can decrease MMP, cell death rate and myocardial oxidative stress/injury in rats with coronary heart disease by increasing vascular FGF-2 and VEGF and enhancing activity of lactate dehydrogenase.