In this paper, this study was conducted to identify the relationship of fatigue, stress, social support, self-efficacy and meaning of life and to investigate the main factors influencing meaning of life in middle adults. The research design was a descriptive survey design using a convenience sampling. Participants were 210 middle adults who were recruited from December 2016 to February 2017. Data analysis was done using SPSS/WIN 21.0 program for descriptive statistics, Pearson correlation coefficients and stepwise multiple regression. The mean score of the meaning of life was 3.41. There were significant correlations between stress, social support, self-efficacy and meaning of life. Stress, social support and self-efficacy were significant predictors explaining 61.7% of the variance in meaning of life. The results indicate that these factors influencing meaning of life should be considered when developing nursing interventions to improve meaning of life for middle adults.