N-acetyltransferase 2 (NAT2) is a polymorphic enzyme that plays an important role in the metabolism of various potential carcinogens. In recent years, a number of studies have been carried out to investigate the relationship between the rs1799930 and rs1799931 polymorphism in NAT2 and cancer risk in multiple populations for different types of cancer. However, the results were not consistent. Therefore, we performed a meta-analysis to further explore the relationship between NAT2 polymorphism and the risk of cancer. A total of 21 studies involving 15, 450 subjects for rs1799930 and 13, 011 subjects for rs1799931 were included in this meta-analysis. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of associations. We also evaluated the publication bias and performed a sensitivity analysis. Overall, our results showed an apparent significant association between the NAT2 rs1799930 polymorphism and cancer susceptibility in Asians (GA vs. GG: OR=1.22, 95% CI=1.03-1.45; dominant model: OR=1.22, 95% CI=1.03-1.43) and population-based controls (GA vs. GG: OR=1.10, 95% CI=1.01-1.19; dominant model: OR=1.09, 95% CI=1.01-1.18). In contrast, a significant association was observed between the NAT2 rs1799931 G>A polymorphism and decreased cancer susceptibility in overall meta-analysis (AA vs. GG: OR=0.55, 95% CI=0.33-0.93; GA vs. GG: OR=1.00, 95% CI=0.88-1.14; dominant model: OR=0.97, 95% CI=0.86-1.10; recessive model: OR=0.56, 95% CI=0.34-0.94) and the Asian group (AA vs. GG: OR=0.50, 95% CI=0.26-0.94; recessive model, OR=0.50, 95% CI=0.27-0.94). We found that the NAT2 rs1799930 may be a risk factor, while the NAT2 rs1799931 polymorphism is associated with a decreased risk of cancer and is likely a protective factor against cancer development.