<b><i>Introduction:</i></b> COVID-19 lockdown measures have large impact on lifestyle behaviors and well-being of children. The aim of this mixed-methods study was to investigate the impact of COVID-19 lockdown measures on eating styles and behaviors, physical activity (PA), screen time, and health-related quality of life (HRQoL) in children (0–18 years) with severe obesity. <b><i>Methods:</i></b> During the first COVID-19 wave (April 2020), validated questionnaires were completed and semi-structured telephone interviews were conducted with parents of children with severe obesity (adult body mass index [BMI]-equivalent ≥35 kg/m²) and/or with the children themselves. Changes in pre-pandemic versus lockdown scores of the Dutch Eating Behavior Questionnaire Children, Pediatric Quality of Life Inventory, and Dutch PA Questionnaire were assessed. Qualitative analyses were performed according to the Grounded Theory. <b><i>Results:</i></b> Ninety families were approached of which 83 families were included. Characteristics of the included children were: mean age 11.2 ± 4.6 years, 52% female, mean BMI SD-score +3.8 ± 1.0. Emotional, restrained, and external eating styles, HRQoL, and (noneducational) screen time did not change on group level (all <i>p</i> &#x3e; 0.05). However, weekly PA decreased (mean difference −1.9 h/week, <i>p</i> = 0.02) mostly in adolescents. In the majority of children, mean weekly PA decreased to ≤2 h/week. Children with high emotional or external eating scores during lockdown or pre-existent psychosocial problems had the lowest HRQoL (<i>p</i> &#x3c; 0.01). Qualitative analyses revealed an increased demand for food in a significant proportion of children (<i>n</i> = 21), mostly in children &#x3c;10 years (19/21). This was often attributed to loss of daily structure and perceived stress. Families who reported no changes (<i>n</i> = 15) or improved eating behaviors (<i>n</i> = 11) attributed this to already existing strict eating schemes that they kept adhering to during lockdown. <b><i>Conclusion:</i></b> This study shows differing responses to COVID-19 lockdown measures in children with severe obesity. On group level, PA significantly decreased and in substantial minorities eating styles and HRQoL deteriorated. Children with pre-existent psychosocial problems or pre-pandemic high external or emotional eating scores were most at risk. These children and their families should be targeted by health care professionals to minimize negative physical and mental health consequences.