Abstract Aim: This study investigates the impact of social isolation, weight changes, and physical activity (PA) by the electronic tools (eTools) on the quality of life (QoL) of Brazilian medical students during the COVID-19 pandemic. Methods: In this observational longitudinal study, one hundred eighty-nine medical students completed an e-questionnaire, which used the WHOQOL-Bref instrument to report QoL and sociodemographic characteristics, health conditions, and lifestyles related to PA. Cronbach's alpha and Friedman/Dunn and Spearman's correlation tests were performed. Based on descriptive and inferential statistics, a multiple linear regression was used to evaluate the potential predictors of QoL. Results: The COVID-19 pandemic particularly affected the psychological and social domains. Time spent indoors and a non-ideal BMI had a negative impact on QoL. Being female and sexual minority-group membership were associated with lower QoL scores in the psychological and physical domains, respectively. Access to PA eTools was positively associated with QoL. Being monitored by a physical education teacher contributes to satisfactory PA levels during online classes. Conclusion: This study provides novel insights into the access of PA eTools on QoL during the COVID-19 pandemic. During periods of social distancing, people should pay extra attention to self-care strategies to protect mental health and promote positive lifestyle patterns. In addition, using online PA resources monitored by physical education teachers could be a strategy to maintain satisfactory levels of exercise.