Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but risk stratification and final outcomes remain suboptimal. In this study, we identify and validate targetable metabolic drivers relevant to the prognosis of patients with rectal cancer treated with CCRT. Using a published transcriptome of rectal cancers, we found that asparagine synthetase (ASNS) gene significantly predicted the response to CCRT. From 172 patients with rectal cancer, the expression levels of ASNS, using immunohistochemistry assays, were further evaluated in tumor specimens initially obtained by using colonoscopy. Expression levels of ASNS were further correlated with major clinicopathological features and clinical survivals in this valid cohort. ASNS deficiency was significantly related to advanced posttreatment tumor (T3, T4; P = .015) and nodal status (N1, N2; P = .004) and inferior tumor regression grade (P < .001). In survival analyses, ASNS deficiency was significantly associated with shorter local recurrence-free survival (LRFS; P = .0039), metastasis-free survival (MeFS; P = .0001), and disease-specific survival (DSS; P = .0006). Furthermore, ASNS deficiency was independently predictive of worse outcomes for MeFS (P = .012, hazard ratio = 3.691) and DSS (P = .022, hazard ratio = 2.845), using multivariate analysis. ASNS deficiency is correlated with poor therapeutic response and worse survivals in patients with rectal cancer receiving neoadjuvant CCRT. These findings indicate that ASNS is a prognostic factor with therapeutic potential for treating rectal cancer.