Children's ego-resilience (within-person capacities that facilitate psychological resistance) and irritability (increased proneness to experience negative affective states following environmental stressors) are critical determinants of their mental health. Here, we investigated how ego-resilience engages with irritability when linked to symptoms of anxiety and depression. We analyzed cross-sectional survey data from a combined clinical and nonclinical sample. Overall, 228 German children (M[subscript age] = 12.52, SD[subscript age] = 2.69; 41.7% female) reported on symptoms of depression/anxiety, ego-resilience, and irritability. Moderated hierarchical regression analyses showed that ego-resilience was negatively associated with symptoms of anxiety and depression and that irritability was positively related to heightened symptom levels. Ego-resilience and irritability had overall stronger associations with symptoms of depression than anxiety. Irritability moderated the association between ego-resilience and depression, such that the effects of ego-resilience were stronger among highly irritable children. We discuss our findings within environmental and biological sensitivity frameworks. Future research must substantiate our findings and determine whether sensitivity frameworks help better understand the potentially interrelated impact of ego-resilience with irritability on children's mental health.