Mindfulness and relaxation exercises are effective face-to-face interventions for reducing distress in people with cancer. Their effectiveness in mobile health settings has yet to be investigated. This study evaluated the effectiveness of the CanRelax 2 app in reducing distress in people with cancer. German-speaking adults diagnosed with cancer within the last five years with elevated distress levels (Distress Thermometer ≥5) were recruited. Participants were randomized to the CanRelax 2 app or a waitlist control group. The primary endpoint was the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) after 10 weeks (210 participants). We observed a clinically meaningful larger reduction in PHQ-ADS scores in the intervention group compared to the control group (-3.7, 95%-CI from -5.7 to -1.6; p = 0.0005). Similar effects were found for distress, well-being, and self-regulation. Our results confirm the effectiveness of a mobile health app in reducing distress in people with cancer. Registration: German Clinical Trials Register (DRKS00027546) on 23.02.2022.