The Covid-19 pandemic obliged people around the world to stay home and self-isolate, with a number of negative psychological consequences. This study focuses on the protective role of character strengths in sustaining mental health and self-efficacy during lockdown. Data were collected from 944 Italian respondents (mean age = 37.24 years, SD = 14.50) by means of an online survey investigating character strengths, psychological distress and Covid-19-related self-efficacy one month after lockdown began. Using principal component analysis, four strengths factors were extracted, namely transcendence, interpersonal, openness and restraint. Regression models showed that transcendence strengths had a strong inverse association with psychological distress, and a positive association with self-efficacy. Openness showed an unexpected direct effect on psychological distress. These results provide original evidence of the importance of character strengths, and transcendence strengths in particular, in supporting mental health and self-efficacy in a pandemic and are discussed within the field of positive psychology.