Nursing is a high-risk occupation with high exposure to stress. The physical and mental health of nurses is directly related to the quality of medical services. Therefore, the sleep quality of nurses should not be ignored. In this study, the method of cluster random sampling was adopted from May to September 2019, and a questionnaire survey was conducted among 521 surgical nurses from five affiliated hospitals of Xinjiang Medical University. The relationship between mental health and sleep quality was analyzed, and 20% of the participants with sleep disorders were randomly selected. The sleep disorders used 1 : 1 matching, finally providing a sample with 60 cases and 60 controls for measurement of the gene (rs1801260, rs6850524), to analyze the effect of the interaction between mental health and the gene on sleep. The mental health and sleep quality of the surgical nurses were evaluated using the Symptom Checklist 90 (SCL-90) and Pittsburgh Sleep Quality Index (PSQI). The study found that surgical nurses had poor sleep, and there were differences associated with age, years working, frequency of night shifts, and incidence of sleep disorders under marital status ( < 0.05). The PSQI scores of the positive psychological symptoms were higher than those of the negative psychological symptoms. The rank sum test was used to compare the sleep quality scores of different genotypes in rs1801260 and rs6850524; the results indicated that the PSQI scores were different among different genotypes at the rs1801260 and rs6850524 loci. The logistic regression results suggested that gene rs1801260 (TC) and positive psychological symptoms were influential factors for sleep disorders, and the interaction of positive psychological symptoms∗rs1801260 (TT) was a risk factor for sleep disorders (OR = 10.833, 95% CI: 2.987-39.288). The sleep quality of nurses is not only affected by demographic characteristics but also affected by mental health status and the gene.