The global pandemic caused by COVID-19 and the subsequent lockdown have been widely recognized as traumatic events that pose threats to psychological well-being. Recent studies reported that during such traumatic events, women tend to be at greater risk than men for developing symptoms of stress, anxiety, and depression. Several studies reported that a mindfulness-based stress reduction protocol (MBSR) provides useful skills for dealing with traumatic events. In our study, a sample of Italian females received an 8-week MBSR course plus 6 weeks of video support for meditation practice during the first total lockdown in Italy. We assessed the participants with questionnaires before and after this period to investigate their mindfulness skills, psychological well-being, post-traumatic growth, and psychological flexibility. After the intervention, the meditators group reported improvement in measures associated with self-acceptance, purpose in life, and relation to others compared to the control group. Furthermore, our results showed that participants with greater mindfulness scores showed high levels of psychological flexibility, which in turn was positively associated with higher levels of psychological well-being. We concluded that the MBSR could support psychological well-being, at least in female subjects, even during an unpredictable adverse event, such as the COVID-19 lockdown, by reinforcing key psychological aspects.