Objective: This study aimed to evaluate the psychological impacts of COVID-19 prevention measures, such as social isolation, on a Mexican sample. Methods: We conducted an online sociodemographic and Impact of Event Scale-Revised (IES-R) survey during the second phase of the COVID-19 outbreak in Mexico to evaluate the presence of psychological distress, signs of post-traumatic stress, and to identify the groups at highest risk in the sample. Results: Prevalence of psychological distress at moderate or severe levels in the sample were as follows: 943 (22%) intrusive thoughts, 933 (22.3%) avoidance, and 515 (12.2%) hyperarousal. Furthermore, we found the symptoms of clinically significant post-traumatic stress in 1160 (27.7%) of the participants. The variables positively correlated with higher psychological distress were as follows: age (younger), sex (female), employment (employed), relationship status (single), in social isolation, number of days in isolation, the number of people in the household (3-5), and a perception of a high risk of contracting COVID-19, change in routine, engaging in less activity, and loss of income. Conclusion: During phase 2 of the COVID-19 outbreak in Mexico, we observed the presence of psychological distress and post-traumatic stress symptoms in over a quarter of the population. This investigation may guide mental health interventions and policies towards the groups that are most vulnerable to the impacts of the social and lifestyle changes taking place in Mexico due to COVID-19.