Increased reactivity to daily stressors is associated with mental health difficulties, which are common in autistic individuals. We investigated affective reactivity to daily-life stress, cognitive emotion regulation, and their link with co-occurring mental health symptoms in adolescents and young adults with autism. A 6-day ecological momentary assessment protocol was used to assess perceived daily-life stress (event-related, activity-related, and social stress) as well as negative affects in autistic ( n = 39, age = 18.4) and non-autistic ( n = 55, age = 18.1) participants. Co-occurring mental health difficulties, social functioning, and cognitive emotion regulation were assessed with questionnaires and clinical evaluations. Youth with autism showed higher levels of perceived stress related to their daily social context and activities, as well as an increased affective reactivity to activity-related stressors compared with non-autistic youth. Moreover, they reported using less adaptive and more non-adaptive emotion regulation, the latter increasing their affective response to daily stressors and possibly contributing to the severity of co-occurring mental health symptoms. Our findings demonstrate high perceived daily-life stress in autistic adolescents and young adults. To minimize the negative effects of stress and the development of mental health symptoms, interventions could focus on effective stress management and strategies that autistic young people use to manage their emotions. Lay abstract Previous research has shown that autistic individuals report high levels of perceived stress and have an increased likelihood of developing mental health difficulties. Increase in individuals’ negative emotions in relation to perceived stress (i.e. affective reactivity to stress) is a known risk factor for mental health difficulties. In this study, we investigated perceived daily stress and affective reactivity to stress in autistic ( n = 39, age = 18.4) and non-autistic ( n = 55, age = 18.1) adolescents and young adults. We used the ecological momentary assessment, a technique that allows to assess individuals repeatedly in their daily life using their smartphone. Moreover, participants filled a questionnaire to evaluate the strategies they use to regulate emotions when faced with difficulties. Finally, a clinical interview and a parent-report questionnaire were used to assess mental health symptoms. Autistic youth reported higher levels of perceived daily stress compared with non-autistic peers. Moreover, they showed increased affective reactivity to stress related to their daily activities. Autistic participants reported more emotion regulation difficulties (e.g. more repetitive thinking of difficulties) compared with non-autistic participants. Difficulties in emotion regulation increased negative emotions in relation to stress and might contribute to the severity of mental health symptoms. We conclude that adolescents and young adults with autism report high perceived stress in their daily lives. To minimize the negative impact of stress and the development of mental health symptoms, people supporting autistic young people could focus on stress management skills and the strategies that the youth use to manage emotions.