Background: Multiple genetic and environmental factors influence the severity of NIHL. However, few studies have reported interactions among such factors in modulating the risk of NIHL. This study aimed to assess for interactions among gene polymorphisms, noise metrics, and lifestyles on the risk of NIHL.Methods: A case-control study was conducted using 307 patients with NIHL and 307 matched healthy individuals from five manufacturing industries. General demographic data, lifestyle details, and noise exposure levels were recorded. The kompetitive allele-specific polymerase chain reaction (KASP) was used to analyze the genotypes of 18 single nucleotide polymorphisms (SNPs). The generalized multifactor dimensionality reduction (GMDR) method was used to examine the effects of all possible interactions. Results: The proportion of people with complex noise exposure, high CNE, high adj-CNE, smoking, propensity to watch loud videos, or sedentary lifestyle was significantly greater in the NIHL group than in the healthy group (P < 0.05). The GMDR model demonstrated a relevant interaction between NRN1 rs3805789 and CAT rs7943316. Subjects with the SNP pair of NRN1 rs3805789-CC and CAT rs7943316-AT, NRN1 rs3805789-CT and CAT rs7943316-AA, NRN1 rs3805789-CT and CAT rs7943316-TT, NRN1 rs3805789-CT/TT and CAT rs7943316-AA, or NRN1 rs3805789-CC and CAT rs7943316-AT/TT had higher risks of NIHL than those with NRN1 rs3805789-CC and CAT rs7943316-AA (P < 0.05). There was an interaction among NRN1 rs3805789, CAT rs7943316, and kurtosis. Subjects exposed to complex noise and carrying both NRN1 rs3805789-CT and CAT rs7943316-TT or NRN1 rs3805789-CT/TT and CAT rs7943316-AA had higher risks of NIHL than those exposed to steady noise and carrying both NRN1 rs3805789-CC and CAT rs7943316-AA (P < 0.05). The best six‐locus model involving NRN1 rs3805789, CAT rs7943316, smoking, video volume, physical exercise, and working pressure for the risk of NIHL was found to be the interaction (P = 0.0010). An interaction was also found among smoking, video volume, physical exercise, working pressure, and kurtosis (P = 0.0107).Conclusions: Complex noise, high CNE, high adj-CNE, smoking, high video volume, and sedentary lifestyle are environmental risk factors for NIHL. Concurrence of NRN1 rs3805789 and CAT rs7943316 constitutes a genetic risk factor for NIHL. Complex noise exposure significantly increases the risk of NIHL in subjects with a high genetic risk score. Interactions between genes and lifestyle as well as noise metrics and lifestyle affect the risk of NIHL. These results provide a theoretical basis for screening genetic and environmental risk factors to prevent NIHL.