(1) Background: Acute kidney injury (AKI) is a common complication following thoracic aortic surgery (TAS), with moderate hypothermic circulatory arrest (MHCA). However, prediction of AKI with classical tools remains uncertain. Therefore, it was the aim of the present study to evaluate the role of new biomarkers in patients after MHCA. (2) Methods: 101 consecutive patients were prospectively enrolled. Measurements of urinary [TIMP-2]*[IGFBP7] and Cystatin C in the blood were performed perioperatively. Primary endpoint was the occurrence of AKI stage 2 or 3 (KDIGO-classification) within 48 h after surgery (AKI group). (3) Results: Mean age of patients was 69.1 ± 10.9 years, 35 patients were female (34%), and 13 patients (13%) met the primary endpoint. Patients in the AKI group had a prolonged ICU-stay (6.9 ± 7.4 days vs. 2.5 ± 3.1 days, p < 0.001) as well as a higher 30-day-mortality (9/28 vs. 1/74, p < 0.001). Preoperative serum creatinine (169.73 ± 148.97 μmol/L vs. 89.74 ± 30.04 μmol/L, p = 0.027) as well as Cystatin C (2.41 ± 1.54 mg/L vs. 1.13 ± 0.35 mg/L, p = 0.029) were higher in these patients. [TIMP-2]*[IGFBP7] increased significantly four hours after surgery (0.6 ± 0.69 mg/L vs. 0.37 ± 0.56 mg/L, p = 0.03) in the AKI group. Preoperative Cystatin C (AUC 0.828, p < 0.001) and serum creatinine (AUC 0.686, p = 0.002) as well as [TIMP-2]*[IGFBP7] 4 h after surgery (AUC 0.724, p = 0.020) were able to predict postoperative AKI. The predictive capacity of Cystatin C was superior to serum creatinine (p = 0.0211) (4) Conclusion: Cystatin C represents a very sensitive and specific biomarker to predict AKI in patients undergoing thoracic surgery with MHCA even before surgery, whereas the predictive capacity of [TIMP-2]*[IGFBP7] is only moderate and inferior to that of serum creatinine.