Introduction Diabetic patients may develop diabetic cardiomyopathy (DCM) and are at increased risk of myocardial infarction (MI). Yet, cardioprotection remains a challenge in the presence of comorbidities. Objectives We examined whether intravenous administration of atorvastatin during ongoing myocardial ischemia prevents against the deleterious effects of MI in DCM rats. Methods DCM was induced by streptozotocin (65 mg/kg) in Sprague Dawley rats (n = 14). 5 weeks thereafter animals exhibited a DCM phenotype associated with a significant diastolic (IVRT + 15.64 ± 5.49ms P < 0.05 vs. baseline) and systolic (LVEF, −8.63 ± 6.71% P < 0.05 vs. baseline) ventricular dysfunction. AMI was then induced by coronary ligation of the LAD for 45minutes. Early after ischemia (15minutes) DCM-rats received either i.v atorvastatin or vehicle. Animals were reperfused and sacrificed at 24h for infarct size assessment and molecular analysis. Cardiac function was monitored by echocardiography. Results No differences were detected as per the area-at-risk between both animal groups. Atorvastatin significantly reduced infarct size expansion (35% relative reduction) as compared to vehicle (15.3 ± 1.03% vs. 23.7 ± 4.3% IS/AAR; P < 0.05). LVEF, shortening fraction, and stroke volume were better preserved in atorvastatin-treated DCM rats as compared to vehicle (4.62 ± 2.55% vs. 12.4 ± 3.16%; 5.77 ± 3.74% vs. 15.9 ± 4.9%; and 58.93 ± 28.79μl vs. 101.73 ± 31.58 μl, respectively; P < 0.05). At a molecular level, atorvastatin administration was associated with a lower expression of Phosphorylated-p53 (apoptosis) and higher P-AMPK/AMP ratio (cardiac metabolism); P < 0.05 vs. vehicle). Conclusion Intravenous administration of atorvastatin during MI limits infarct size and preserves cardiac function post-MI in rats with manifest DCM supporting the cardioprotective potential of this therapeutic approach despite comorbid conditions.