Large-scale health crises, such as the COVID-19 pandemic, may evoke negative affective responses, which are linked to psychological maladjustment and psychopathology. Here, we shed light on the role of the personality trait neuroticism in predicting who experiences negative affective responses. In a large-scale experience-sampling study (N = 1,609; 38,120 momentary reports), we showed that individuals high in neuroticism experienced more negative affect and higher affective variability in their daily lives. Individuals high in neuroticism also (a) paid more attention to COVID-19-related information and worried more about the consequences of the pandemic (crisis preoccupation), and (b) experienced more negative affect during this preoccupation (affective reactivity). These findings offer new insights into the consequences and dynamics of neuroticism in extreme environmental contexts.