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On 10 March 2020, in Italy, a total lockdown was put in place to limit viral transmission of COVID-19 infection as much as possible. Research on the psychological impact of the COVID-19 pandemic highlighted detrimental effects in children and their parents. However, little is known about such effects in children with neurodevelopment disorders and their caregivers. The present study investigated how the lockdown has impacted the physiological and psychological well-being of children with Fragile X-Syndrome (FXS), aged from 2 to 16 years, and their mothers. In an online survey, 48 mothers of FXS children reported their perception of self-efficacy as caregivers and, at the same time, their children’s sleep habits, behavioral and emotional difficulties during, and retrospectively, before the lockdown. Results showed a general worsening of sleep quality, and increasing behavioral problems. Although mothers reported a reduction in external support, their perception of self-efficacy as caregivers did not change during the home confinement compared to the period before. Overall, the present study suggested that specific interventions to manage sleep problems, as well as specific therapeutic and social support for increasing children and mother psychological well-being, need to be in place to mitigate the long-term effects of a lockdown.