Background: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 15–30% of patients achieve a pathological complete response. Single nucleotide polymorphisms represent stable genetic markers with potential predictive value for treatment response. This systematic review synthesizes current evidence on the association between SNPs and the response to nCRT in rectal cancer. Methods: PubMed and Web of Science databases were searched for relevant English studies. Two reviewers independently screened the titles and abstracts using the DistillerSR tool. Full-text articles were assessed for their eligibility. Data extraction followed the PRISMA guidelines, and the risk of bias was assessed. Results: Thirty-two studies (4116 patients) assessed 304 SNPs across 126 genes in 407 analyses. DNA repair genes (XRCC1, XRCC3, ERCC1, ERCC2) and folate metabolism genes (MTHFR, TYMS) were most frequently investigated. Only two SNPs demonstrated predictive value in multiple studies: rs25487 (XRCC1) and rs1801133 (MTHFR); however, the associations were inconsistent. The remaining SNPs showed isolated associations in single studies. No SNP demonstrated predictive value across independent cohorts. Conclusions: Current evidence does not support the clinical use of individual SNPs to predict nCRT response in rectal cancer patients. Although XRCC1 and MTHFR polymorphisms have been extensively studied, their predictive utility remains inconclusive. Future research should prioritize large, multicenter prospective studies with standardized treatment and outcome definitions, and consider polygenic risk models or integrated multi-omic approaches.