Background: As the COVID-19 pandemic progresses, mental health begins to be affected. In this sense, practical and low-cost solutions are necessary to minimize the impact on the population. Aim: This study aimed to determine the effect of a mindfulness-based online intervention for mental health during times of COVID-19. Method: A quasi-experimental study was carried out with pre-test and post-test measurements in a sample of 62 participants divided into an experimental group whose members were administered a 12-session mindfulness online program, and a control group on the waiting list. The Zung Self-Rating Anxiety Scale (SAS) was used to assess anxiety, the Zung Self-Rating Depression Scale (SDS) to measure depression, and the Perceived Stress Scale (PSS-14) to determine stress levels. Results: The levels of anxiety, depression, and stress decreased after the intervention, finding significant differences between the groups and study phases (P < 0.05). In addition, moderate changes in anxiety (d = 0.849, g = 0.847) and depression (d = 0.533, g = 0.530) were found, as well as important changes in stress reduction (d = 1.254, g = 1.240). Conclusion: There is evidence of a potential for the use of mindfulness program to reduce stress, anxiety, and depressive symptoms in stressful situations such as the COVID-19 pandemic.