Background Childhood experiences of neglect hinder the healthy development of secondary school students and affect their quality of life. We aimed to assess the relationship between childhood neglect, core self-evaluation, and quality of life to provide reliable evidence to support secondary school students. Methods A stratified random sample of 1692 students from four general middle and high schools in Xiamen in June 2020 were surveyed using the Childhood Neglect Scale (CNS), the Core Self-Esteem Scale (CSES), and the Quality of Life Scale for Children and Adolescents (QLSCA), and the data were analyzed and tested for mediating effects using SPSS 23.0. Results 15.1% of secondary school students experienced neglect in childhood, of which 19.7% had emotional neglect, 26.4% had safety neglect, 16.5% had communication neglect, and 27.7% had physical neglect. Child neglect was significantly and positively correlated with its factors, child neglect and its factors were significantly and negatively correlated with core self-evaluation, and core self-evaluation and quality of life were significantly positively correlated with quality of life. There was a partially mediating effect of core self-evaluation of secondary school students on the effect between child neglect and its factors (emotional neglect, safety neglect, communication neglect, and physical neglect) and quality of life, and the proportion of the mediating effect to the total effect was 45.73%, 49.61%, 46.59%, 54.64%, and 49.06%, respectively. Conclusions Core self-evaluation of secondary school students partially mediated the effect between child neglect and quality of life, and child neglect affected secondary school students' quality of life through core self-evaluation.