The COVID-19 pandemic has had a significant impact on the quality of life (QoL), daily lifestyle, and mental health of people suffering from a mental disorder. This study aimed to investigate the effects of the prolongation of the COVID-19 emergency on QoL and lifestyles in a sample of 100 outpatients at the Psychiatry Unit in Palermo University Hospital, Italy. QoL was measured through the 12-item Short Form Survey and the COV19-Impact on Quality of Life. Lifestyle changes during the pandemic were measured through the lifestyle change questionnaire. The majority of participants reported a great impact of COVID-19 on the QoL, and almost half reported worsened lifestyles. Worsened lifestyles were predictive of both poor mental and physical health related QoL. These results suggest that people with mental illness need interventions targeting lifestyles, and the mental health service in Italy should adjust to the ongoing pandemic, developing virtual treatments.