Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction leading to obesity and behavioral disabilities, including eating disorders (EDs). We evaluated the effects of the COVID-19 infection and lockdown on mental and physical health in PWS. At the end of April, 85 adults with PWS completed a self-administered questionnaire, including lockdown conditions, physical activity (PA), ED, and medical and behavioral outcomes. Body weight was measured at home and self-reported. Results: Patients (52.9% women, 44.8% disomic) were assessed, with a mean age of 28.05 ± 8.73 years and body mass index (BMI) of 36.76 ± 10.74 kg/m2. Seventy percent lived in the Paris region (France) and were confined with their parents. The mean weight change was 0.96 ± 3.28 kg. We compared patients showing weight loss (n = 39, - 3.30 ± 2.93 kg) to patients showing weight gain (n = 22, + 2.35 ± 1.54 kg): the BMI was lower (34.60 ± 9.18 versus 40.45 ± 9.45 kg/m2, p = 0.02), PA increased (25.6% versus 4.5%, p = 0.04), and EDs improved (51.3% versus 13.6%, p = 0.005). Behavioral disorders increased for 12.9% of the cohort. Three individuals (3.5%) were diagnosed with non-severe COVID-19. Conclusion: Lockdown during the COVID-19 pandemic was associated with positive effects for most French adults with PWS, with weight loss probably associated with a more favourable environment during this period. We observed no severe forms of COVID-19.