The effect of different SNPs in HIF-1α and cancer susceptibility remain indistinct. Here, we evaluated the association between all identified SNPs (rs11549465, rs11549467 and rs2057482) in HIF-1α and the overall risk of cancer in all case-control studies published before April 2020. A total of 54 articles including 56 case-control studies were included in this analysis. We found that variant genotypes of rs11549465 and rs11549467 were associated with a significantly increased overall cancer risk. In contrast, the variant T allele of rs2057482 showed a significantly reduced risk of overall cancer. In addition, variant genotypes of the three studied SNPs exhibited a significant association with cancer risk in Asians and specific cancer types. Meanwhile, HIF-1α was significantly highly expressed in head and neck squamous cell carcinoma and pancreatic cancer tissues. More importantly, survival analysis indicated that the high expression of HIF-1α was associated with a poor survival in patients with lung cancer. These findings further provided evidence that different SNPs in HIF-1α may exhibit different effects on overall cancer risk; these effects were ethnicity and type-specific. Further studies with functional evaluations are required to confirm the biological mechanisms underlying the role of HIF-1α SNPs in cancer development and progression.