Background: Chronic stress is associated with accelerated aging and poor health outcomes in older adults. According to the Transactional Model of Stress (TMS), distress is experienced when one perceives the stressor, or threat, to outweigh the ability to cope. The experience of distress is correlated with trait neuroticism, which is associated with greater perceptions of stress and stress reactivity, as well as a tendency to engage in maladaptive coping strategies. However, as individual personality traits do not act in isolation, this study aimed to investigate the moderating role of self-esteem in the relationship between neuroticism and distress using a TMS framework. Methods: A total of 201 healthy older adults (Mage = 68.65 years) completed questionnaires measuring self-esteem, neuroticism, perceived stress, and positive coping. Results: Greater neuroticism was significantly associated with less positive coping at low (b = −0.02,p< 0.001) and mean self-esteem levels (b = −0.01,p< 0.001), but not at high self-esteem levels (b = −0.01,p= 0.06). No moderating effect was found for perceived stress or overall distress. Conclusion: The results support the association between trait neuroticism and indices of stress and suggest a potential buffering effect of self-esteem in moderating the negative association between neuroticism and positive coping.