Background: The impact of coronavirus disease (COVID-19) on public mental health in 2019 is verified, but the role of only-child status in the mental health of adolescents confined at home during the COVID-19 epidemic has not been investigated and is not clear. Objective: Our study aims to assess the impact of only-child status on the mental health of adolescents confined at home during the COVID-19 outbreak. The exposure risk to COVID-19, adverse experience, parent-child relationship, and resilience have also been measured and considered. Methods: From March 20 to 31, 2020, a cross-sectional survey test was conducted on 11,681 adolescents aged from 12 to 18 years in middle schools (Grade 7 to Grade 9) across five provinces in China. The self-reported online questionnarie was used to collected data of demographic information, the 9-item Patient Health Questionnaire, the 7-item Generalized Anxiety Disorder Scale, the short form of the Childhood Trauma Questionnaire, the Connor-Davidson Resilience Scale and the exposure risk to COVID-19. Results: A total of 11,180 valid questionnaires were collected, with an effective rate of 95.7%. 35.2% of only children and 38.8% of non-only children reported depression symptoms, while 20.5% of only children and 24.7% of non-only children reported anxiety symptoms. It was significant that non-only children were more likely to have anxiety and depression symptoms than only children (OR = 1.164, 95%CI: 1.064-1.273, p = 0.001). The risk of exposure to COVID-19 was a risk factor of depression (OR = 2.284, 95%CI: 1.640-3.180, p < 0.001) and anxiety symptoms (OR = 1.959, 95%CI: 1.402-2.737, p < 0.001) in non-only children, but not in only children. For both only children and non-only children, the resilience and parent-child relationship were protective factors of depression and anxiety symptoms, while emotional abuse was a risk factor (p < 0.001). Conclusion: The non-only children are more likely to develop the symptoms of anxiety and depression than only children, during the outbreak of COVID-19 in China. The adolescents with siblings are psychiatrically more vulnerable to exposure risk of COVID-19 and need more attention, especially those with poor parent-child relationship, low resilience and experience of emotional abuse.