SummaryDue to the high morbidity and mortality of colorectal cancer (CRC), this study aims to determine the joint association of RE‐1‐silencing transcription factor (REST) and nuclear factor‐κB 1 (NFKB1) genes with CRC in a population‐based study. A well‐matched case‐control study including 390 controls and 388 patients with CRC was enrolled in China. The selected single nucleotide polymorphisms (SNPs) in the REST and NFKB1 genes were genotyped by Illumina SnapShot Chip. After adjustment for important covariates, the associations of SNPs and joint association of REST and NFKB1 with CRC were evaluated by multiple logistic regression models. The subjects with the rs2228991 AA genotype of the REST gene had a decreased risk for CRC (OR = 0.38; 95%CI: 0.19–0.74), compared with the GG genotype. There were no significant associations between three SNPs in the NFKB1 gene, their haplotype and CRC risk. However, a significant combined effect of rs3774959 and rs3774964 in the NFKB1 gene with rs2228991 in the REST gene on CRC risk was observed. In conclusion, the present study found that mutation in the REST gene rather than the NFKB1 gene was associated with the risk of CRC. Furthermore, significant REST‐NFKB1 joint association was observed for CRC, colon cancer and rectal cancer risk.