Special attention and efforts to protect from or reduce health-related outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus triggering coronavirus disease 2019 (COVID-19), should be applied in susceptible populations, including frail older people. In particular, the early death cases occurred primarily in older people with a frailty status, possibly due to a weaker immune system fostering faster progression of the viral infection. Frailty is an age-related multidimensional clinical condition defined as a non-specific state of vulnerability, identifying older people at increased risk of falls, institutionalization, hospitalization, disability, dementia, and death. Among frailty phenotypes, social frailty has been least studied. It considers the role of socioeconomic context as a vulnerability status later in life. COVID-19 does not affect all populations equally, and social inequalities contribute to drive the spread of infections. It was known that the perception of social isolation, e.g., loneliness, affects mental and physical health, but the implicated molecular mechanisms, also related to the immune system, and its associated cognitive and health-related sequelae, are poorly understood. The increasing psychological distress derived by prolonged exposure to stress due to the lockdown scenario, and the reduced sources of support, contributed to making heavy demands on personal resources, i.e., self-efficacy and interpersonal variables. So, perceived loneliness may be a factor associated with psychological distress and an outcome in itself. In the COVID-19 pandemic era, a correct assessment of social frailty may be essential in terms of the prevention of late-life neuropsychiatric disorders.