Individuals vary greatly in their mental health and these differences may play a critical role in stress resistance, risk reduction and illness recovery. Here we ask how these differences may be related to normal variation in personality and genotype. One hundred healthy college students completed measures of mental health (Mental Health Continuum-Short Form [MHC-SF]), personality (NEO Five Factor Inventory) and adverse childhood experiences. Participants also provided saliva samples, genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF), each assayed for naturally occurring polymorphisms, 5-HTTLPR (short/long) and BDNF (valine/methionine). Mental health correlated strongly with the NEO triad of conscientiousness-extraversion-neuroticism, with largest contributions to MHC-SF scores for conscientiousness, followed by extraversion and then neuroticism. The personality trait interaction of extraversion × conscientiousness uniquely accounted for approximately 44.22% 44.62% of the variance in MHC-SF scores. Polygenic comparisons showed a significant gene × gene interaction, with highest mental health for 5-HTTLPR-S, Met carriers. Together these results provided support for distinct yet interacting roles of personality and genetics in the phenotypical expression of mental health. © 2020 John Wiley & Sons Ltd.