Abstract Background Head and Neck Cancer (HNC) survivors are at increased risk of developing a second primary cancer (SPC). Along with the environmental risk factors, genetic factors have been associated with a potential increased susceptibility to SPC development. We aim to identify the Single Nucleotide Polymorphisms (SNPs) that contribute to SPC development among HNC survivors through a systematic review and meta-analysis. Methods We searched PubMed, Scopus and ISI Web of Science for eligible studies published in English until January 31st, 2020. We included studies reporting primary data that evaluated the association between SNPs and SPC risk in HNC patients. Data were pooled in a random-effect meta-analyses, when at least two studies on the same SNP evaluated the same genotype model. Heterogeneity was assessed using the χ2-based Q-statistics and the I² statistics. Quality of the included studies was assessed using the Q-Genie tool. Results Twenty-one studies, of moderate to good quality, were included in the systematic review. Fifty-one genes were reported across the included studies to have significant associations with an increased SPC risk. Overall, 81 out of 122 investigated SNPs were significantly associated with the SPC risk. Seven studies were included in the meta-analysis, which showed five SNPs associated with an increased risk of SPC: p21C70T, CT + TT (HR = 1.76; 95% CI: 1.28–2.43); FASLG -844C > T, CT + TT (HR = 1.82; 95% CI: 1.35–2.46), P21 C98A, CA + AA (HR = 1.75; 95% CI: 1.28–2.38); FAS -670A > G (HR = 1.84; 95% CI: 1.28–2.66) and GST-M1, Null genotype (HR = 1.54; 95% CI: 1.13–2.10). Conclusions The identified SNPs in our systematic review and meta-analysis might serve as potential markers for identification of patients at high risk of developing SPC after primary HNC. PROSPERO Registration Number CRD42019135612.