Abstract Introduction Acute kidney injury (AKI) following acute myocardial infarction (AMI) is associated with unfavorable prognosis. Endothelial activation and injury were found to play a critical role in the development of both AKI and AMI. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation could serve as independent predictors for AKI in patients with AMI. Methods This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with AMI receiving percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. AKI was defined as elevation of serum creatinine of more than 0.3 mg/dL within 48 hours. Results In total, 13 out of 132 (9.8%) patients with AMI developed AKI within 48 hours. Compared with patients without AKI, patients with AKI had increased plasma levels of Ang-2 (6338.28 ± 5862.77 versus 2412.03 ± 1256.58 pg/mL, P = 0.033) and sTM (7.6 ± 2.26 versus 5.34 ± 2.0 ng/mL, P < 0.001), and lower estimated glomerular filtration rate (eGFR) (46.5 ± 20.2 versus 92.5 ± 25.5 mL/min/1.73 m2, P < 0.001). Furthermore, the areas under the receiver operating curves demonstrated that plasma thrombomodulin (TM) and Ang-2 levels on day 1 of AMI had modest discriminative powers for predicting AKI development following AMI (0.796, P <0.001; 0.833, P <0.001; respectively). Conclusions Endothelial activation, quantified by plasma levels of TM and Ang-2 may play an important role in development of AKI in patients with AMI.