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Objectives: The purpose of this study is to examine the effects of five personality factors and perceived stress on psychological well-being of college students. This study also examines the mediating role of perceived stress in the relationship between the five personality factors and psychological well-being of college students. Methods: The subjects of the study were 210 college students (94 males and 116 females), and a self-report questionnaire was conducted. The data were analyzed using SPSS 22.0. Results: Three personality factors(openness, neuroticism, and agreeableness) and perceived stress were found to have a significant effect on college students’ psychological well-being. Perceived stress partially mediated the relationship between personality factor 2(neuroticism and agreeableness) and psychological well-being. Conclusions: This study should be supported by health education or related efforts that can improve individual personality characteristics and cognitive flexibility by exploring intrapersonal factors that can affect psychological well-being of college students.