Objective To explore the change of serum levels of neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinases-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7) in the early stage of multiple trauma, and their predictive efficacy for acute kidney injury (AKI). Methods The multiple trauma patients admitted between February 2020 and July 2021 were prospectively selected, and they were divided into AKI group and non-AKI group according to whether they developed AKI within 72 h after injury. The serum levels of NGAL, TIMP-2, and IGFBP-7 measured at admission and 12, 24, and 48 h after injury, the Acute Pathophysiology and Chronic Health Evaluation Ⅱ(APACHE Ⅱ) score, intensive care unit duration, rate of renal replacement therapy, and 28-day mortality rate were compared between the two groups. Results A total of 51 patients were included, including 20 in the AKI group and 31 in the non-AKI group. The APACHE Ⅱ at admission (20.60±3.57 vs. 11.61±3.44), intensive care unit duration [(16.75±2.71) vs. (11.13±3.41) d], rate of renal replacement therapy (35.0% vs. 0.0%), and 28-day mortality rate (25.0% vs. 3.2%) in the AKI group were higher than those in the non-AKI group (P<0.05). The serum levels of NGAL and IGFBP-7 at admission and 12, 24, and 48 h after injury in the AKI group were all higher than those in the non-AKI group (P<0.05). For the prediction of AKI, the areas under receiver operating characteristic curves and 95% confidence intervals of serum NGAL, TIMP-2 and IGFBP-7 12 h after injury were 0.98 (0.96, 1.00), 0.92 (0.83, 1.00), and 0.87 (0.78, 0.97), respectively. Conclusion Serum NGAL, TIMP-2, and IGFBP-7 have high predictive efficacy for AKI secondary to multiple trauma, and continuous monitoring of serum NGAL can be used for early prediction of AKI secondary to multiple trauma.