Background: Knowledge on the quality of life (QOL) of civil servants is limited. Therefore, the aims of this study were to investigate the QOL of civil servants, and examine whether occupational stress and job satisfaction mediated the association between neuroticism and QOL in civil servants from Shandong, China. Methods: The cross-sectional study included 559 civil servants aged 27 to 60 years from Shandong province in China. Participants completed questionnaires assessing neuroticism, occupational stress, job satisfaction, and QOL. Structural equation modeling (SEM) was conducted to examine the hypothetical model. Results: Among the civil servants, the average score for QOL was 75.49 ± 14.73. The SEM analysis showed a good fit of the data to the hypothesized model. Neuroticism, occupational stress, and job satisfaction explained 38% of the variance of QOL. Neuroticism was positively correlated with occupational stress and negatively correlated with job satisfaction and QOL. A strong direct effect (− 0.386, P < 0.01) and moderate indirect effect (− 0.133, P < 0.01) of neuroticism on QOL mediated by occupational stress and job satisfaction were observed. In addition, a direct effect (− 0.197, P < 0.01) and an indirect effect (− 0.044, P < 0.01) of occupational stress on QOL mediated by job satisfaction were also observed. Conclusions: Occupational stress and job satisfaction partly mediated the relationship between neuroticism and QOL among Chinese civil servants. Thus, selecting individuals with a low level of neuroticism as civil servants, reducing occupational stress, and increasing job satisfaction may be important measures to improve their QOL.