Objective To summarize the genotypes associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) induced by methazolamide and to provide references for the diagnosis and treatment of SJS and TEN induced by methazolamide. Methods Databases including PubMed, EMbase, CNKI, and WanFang Data were electronically searched from database inception to September 2021. Two reviewers independently screened literature and extracted data, and then a systematic review was performed. Results A total of 18 studies involving 49 patients were included. HLA genetic testing was performed on 37 patients. HLA-B*59:01 was detected in 27 patients, HLA-C*01:02 was detected in 15 patients, and 14 patients carried both genes. Statistical analysis showed that the positive rate of HLA-B*59:01 was 73% (95% CI 0.58 to 0.88) and that of HLA-C*01:02 was 40.5% (95%CI 0.24 to 0.57). The latent time until the symptoms were observed was 14.08 ± 8.77 days, and the mean dosage of methazolamide administered was 88.95±39.45 mg/d. Glucocorticoid and immunoglobulin were the main treatments prescribed. Conclusion Methazolamide can cause SJS and TEN. As the presence of HLA-B*59:01 or HLA-C*01:02 has been reported as a genetic risk factor for these adverse drug reactions, the implementation of genetic screening can effectively reduce their occurrence. Glucocorticoid and immunoglobulin, anti-infectives, should be administered to control the symptoms.