Objective This study was conducted to identify factors related to loneliness during the coronavirus disease-2019 (COVID-19) pandemic and focused on how the fear of COVID-19 infection affects loneliness and the conditional effect of gratitude as a moderator in the relationship among the fear of COVID-19, anxiety, and loneliness.Methods For the analysis of this study, a survey was conducted among 1,500 individuals aged 19 to 69 years living in three metropolitan areas in South Korea. Questionnaires included sociodemographic data, psychological experience and stress associated with COVID-19, Generalized Anxiety Disorder Scale–7, UCLA Loneliness Scale–3, and Gratitude Questionnaire–6. An analysis was conducted by applying SPSS PROCESS macro models 4 and 7.Results First, anxiety mediated the relationship between the fear of COVID-19 infection and loneliness. Second, the effect of the fear of COVID-19 infection on loneliness through anxiety was moderated by gratitude. The higher the gratitude, the more the fear of COVID-19 infection is buffered in the path to anxiety, and the lower the indirect effect on loneliness.Conclusion This suggests that in the context of the COVID-19 pandemic, interventions for psychological problems such as anxiety and loneliness can be carried out through gratitude, a significant protective variable.