Objectives: This study aims to assess (i) the health-related Quality of Life (QoL) of medical students in Lebanon, (ii) its association with their general characteristics, and (iii) to investigate the combined effects of the predictors affecting the quality of life of students. Methods: An observational cross-sectional study was performed over three months, targeting 401 medical students from six universities. The 36-item Short Form survey was used to quantify the different QoL scores. Results: The physical component (PC) domains had higher scores than the mental component (MC) ones (70.2 vs. 55.9). Students aged 30 years or less had higher scores in all the PC domains than older students (70.9 vs. 59.3; p<0.010) but comparable scores in the MC domains (55.6 vs. 59.8; p>0.050). Single students had a significantly higher role-emotional score (63.5 vs. 49.0; p<0.050), and those studying in public universities had greater general health scores (57.7 vs. 53.7; p<0.050). Younger age significantly increased most of the health-related PC scores, and having chronic diseases decreased all the QoL scores except the mental health score. Conclusion: The QoL of medical students was negatively affected during the pandemic, particularly their mental health. Informed educational and health decisions are required to minimize this impact on their academic performance.