Background: The COVID-19 lockdown has been a major stressor for the general population, posing a considerable threat to quality of life (QoL), particularly among university students. Existing research highlights the protective role of dispositional mindfulness (DM) in mitigating stressors; however, its influence on moderating the impact of COVID-19 on QoL remains unknown. We used a longitudinal design to assess the QoL of undergraduate students before and after the COVID-19 lockdown, while also examining the potential moderating effect of DM on this impact. Methods: One hundred eleven Spanish undergraduate students were recruited in 2019, and 103 were followed-up in 2020. Instruments comprised a demographic questionnaire, the World Health Organization Quality of Life BREF (WHOQOL-BREF) inventory to assess QoL, and the Five Facets Mindfulness Questionnaire (FFMQ) to assess DM. Results: Analyses revealed statistically significant differences between the two time points in WHOQOL-BREF: Psychological, Social Relationships, and Environmental. Moderation analyses revealed that the impact of COVID-19 on WHOQOL-BREF Psychological scores was moderated by FFMQ-Observe and FFMQ-Non-judging. Conclusions: The COVID-19 lockdown resulted in a reduction of QoL among undergraduate students, yet this impact was moderated by DM. Specifically, present moment attention to experience (observe) and non-judgmental awareness attenuated the impact of COVID-19 on psychological well-being. Future research should focus on evaluating the protective role of preventive interventions designed to increase DM among undergraduate students.