The COVID-19 pandemic that has hit the world in the year 2020 has put a strain on our ability to cope with events and revolutionized our daily habits. On 9 March, Italy was forced to lockdown to prevent the spread of the infection, with measures including the mandatory closure of schools and nonessential activities, travel restrictions, and the obligation to spend entire weeks in the same physical space. The aim of this study was to assess the impact of the COVID-19 pandemic and lockdown measures on quality of life (QoL) in a large Italian sample, in order to investigate possible differences in QoL levels related to both demographic and pandemic-specific variables. A total of 2251 Italian adults (1665 women, mainly young and middle adults) were recruited via a snowball sampling strategy. Participants were requested to answer to an online survey, which included demographic and COVID-related information items, and the World Health Organization Quality of Life BREF questionnaire (WHOQOL-BREF). The results showed statistically significant differences in QoL depending on a number of variables, including sex, area of residence in Italy, and being diagnosed with a medical/psychiatric condition. To our knowledge, this is the first study to assess QoL during COVID-19 pandemic in Italy, therefore the present findings can offer guidelines regarding which social groups are more vulnerable of a decline in QoL and would benefit of psychological interventions.