BackgroundBurnout among millennial medical students is an important health issue with a possibility of potential professional dissatisfaction. The reason for burnout is multifactorial. The gender of the medical student may play a significant role when choosing a residency specialty and making a career choice. Gender may also influence while establishing the burnout seen in students. Here we tested the association between burnout in medical students based on gender and residency specialty choice during COVID-19.MethodsA multicentric cross-sectional study, using a questionnaire-based survey on the items related to gender, educational interest, status, residency aspiration, changes to career aspiration based on gender, and COVID-19 and an indigenous burnout assessment tool that was administered to all the medical students in the study. Reliability and validity of the tool were assessed, and the burnout was calculated for emotional exhaustion, personal achievement, and depersonalization domain.ResultsA total of 487 medical students (42.5% males, 57.2% females) completed the survey. A higher number of female participants felt that COVID-19 affected their energy levels (68.9%), interest in education (53.2%), and developed reservations about residency specialty of choice (46%); emotional and physical exhaustion (2.88 ± 0.69 & 2.34 ± 0.76) was higher than the male participants (3.16 ± 0.67 & 2.75 ± 0.85).ConclusionMore female participants experienced emotional distress, depersonalization or professional disengagement, and psychological and physical stress and exhaustion due to the COVID-19 pandemic. An important association observed in the study was between residency choice and burnout.Supplementary informationThe online version contains supplementary material available at 10.1007/s11845-022-03016-8.