College student well-being is negatively impacted by the tremendous amount of stress students experience, and fallout from college student stress is posing a significant challenge for institutions of higher education (Castillo & Schwartz, 2013; Hunt & Eisenberg, 2010; Kirsch et al., 2014; Lumley & Provenzano, 2003). The purpose of this study is to develop a better understanding of the role stress mindset plays in the relationships between the personality dimension of neuroticism, primary appraisal, and well-being. Specifically, the relationship between neuroticism and well-being, the mediating role of threat and challenge appraisals on the direct relationship between neuroticism and well-being, and the influence of stress mindset as a moderator on the direct and mediated relationship between neuroticism and well-being. A sample of 457 undergraduate college students enrolled in Health and Wellness Studies (HWS) courses completed four assessments over two time periods, exploring personality (Neuroticism/ NEO-FFI), well-being (Scales of Psychological Well-being; PWB), primary appraisal (Stress Appraisal Measure; SAM) and stress mindset (Stress Mindset Measure; SMM). Students completed the first assessment (T 1) during the second and third week of classes, providing demographics and personality data. The second assessment (T2) during mid-terms (7th--8th weeks) included the PWB, SAM, and SMM. Results reveled a significant negative relationship between neuroticism and well-being was present. Further analysis also indicated threat and challenge appraisal mediated the relationship between neuroticism and well-being. Although there were significant correlations between stress mindset and study variables (Neuroticism, PWB & SAM) existed, stress mindset did not moderate the direct nor indirect relationship between neuroticism and well-being. The lack of influence stress mindset exerted may highlight the need to reframe the benefits of such mindsets in relation to well-being. Study findings inform research on both college student well-being and future development of targeted programing that seeks to increase student well-being.