Background Definitive chemoradiation therapy is an alternative curative treatment for esophageal squamous cell carcinoma (ESCC). The prevalence of anastomotic leakage (AL) after salvage esophagectomy is significantly higher than planned esophagectomy after chemoradiation, which increases operative mortality. Minimizing AL-related mortality requires early detection. Several investigators have demonstrated the role of serum C-reactive protein (CRP) in early AL detection after esophagectomy for decades. However, its value in early AL detection after salvage esophagectomy is unknown. This study aims to evaluate the value of serial serum CRP levels for early AL detection in ESCC patients after salvage esophagectomy. Methods We retrospectively reviewed the medical record of 36 patients diagnosed with thoracic squamous cell esophageal carcinoma who underwent salvage esophagectomy at our hospital between December 2016 and May 2022. The CRP level was measured daily from postoperative day (POD) 1 to 5. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to determine the optimal cutoff value. Results A total of 36 patients underwent salvage esophagectomy. Of these 36 patients, 3 patients (8.3%) were diagnosed with AL. The CRP level on POD 2 to 5 had been significantly associated with the presence of AL. The ROC curve showed the excellent diagnostic accuracy of CRP level on POD 2 to 5, with an area under the curve of 0.98, 0.98, 0.93, and 0.87, respectively. The optimal cutoff value of CRP on POD2 to 5 was 270, 250, 200, and 150 mg/L, respectively, with high sensitivity, specificity, and negative predictive value. Conclusion Postoperative serial CRP level after salvage esophagectomy is a reliable useful tool for early AL detection, similar to other settings of esophagectomy.