Currently, several studies have demonstrated that PRKAA1 polymorphisms conduce to the development of cancer. PRKAA1 gene encodes the AMP-activated protein kinase summit-α1, and plays an important role in cell metabolism. Thus, we performed a systematic review and meta-analysis of all enrolled eligible case-control studies to obtain a precise correlation between PRKAA1 polymorphism and cancer susceptibility.Extensive retrieve was performed in Web of Science, Google Scholar, PubMed, EMbase, CNKI and Wanfang databases up to August 26, 2018. Odds ratios (ORs) and 95% CIs were performed to evaluate the overall strength of the associations in five models, as well as in subgroup analyses, stratified by ethnicity, cancer type or source of control. Q-test, Egger's test and Begg's funnel plot were applied to evaluate the heterogeneity and publication bias. In-silico analysis was performed to demonstrate the relationship of PRKAA1 expression correlated with cancer tissues and survival time.Twenty-two case-control studies from 14 publications were enrolled, with 17,068 cases and 20,871 controls for rs13361707, and 2514 cases and 3193 controls for rs10074991. Overall, we identified that the PRKAA1 rs13361707 polymorphism is not significantly associated with cancer susceptibility under all five genetic models. For rs10074991, we revealed a significant decrease risk in allelic comparison model (B vs. A: OR = 0.774, 95% CI = 0.642-0.931, PAdjust = 3.376*10- 2), heterozygote comparison model (BA vs. AA: OR = 0.779 95%CI = 0.691-0.877, PAdjust = 9.86*10- 10;), and dominant genetic model (BB + BA vs. AA: OR = 0.697 95%CI = 0.533-0.912, PAdjust = 4.211*10- 2;). Evidence from TCGA database and GTEx projects indicated that the expression of PRKAA1 in gastric cancer tissue is higher, compared to normal stomach tissue, as well as it in breast cancer and esophageal squamous cell carcinoma. However, the Kaplan-Meier estimate showed that there is no significant difference of OS and RFS between the low and high PRKAA1 TPM groups in gastric cancer, breast cancer, and esophageal carcinoma.To sum up, PRKAA1 rs13361707 polymorphism is not participant with the increased risk of cancer, while the A allele of PRKAA1 rs10074991 revealed a significant decrease risk.