Objective: We aimed to explore the association between academic stress or motivation and the psychological well-being of medical students during the coronavirus disease-2019 (COVID-19) pandemic. We also explored the effects of their resilience or viral anxiety on this association. Methods: This online surveyed for medical students was done during October 20–28, 2021. Participants’ age, sex, grades, and COVID-19-related experiences were collected. Their symptoms were measured with Stress and Anxiety to Viral Epidemics-6 items, Medical Stress Scale (MSS), intrinsic motivation using Academic Motivation Scale, Connor Davidson Resilience Scale-2 items (CD-RISC2), the 5-item World Health Organization Well-Being Index (WHO-5), and GRIT scale. Results: Among 251 medical students, linear regression performed to explore the predicting factors for psychological well-being or medical stress showed that WHO-5 score was predicted by age (β=0.16, p=0.02) and CD-RISC2 (β=0.29, p<0.001) (F=15.5, p<0.001). In addition, the MSS score was predicted by age (β=0.20, p=0.004), intrinsic motivation (β=-0.31, p<0.001), GRIT (β=0.21, p=0.003), and CD-RISC2 (β=-0.31, p<0.001) (F=15.6, p<0.001). The resilience of medical students partially influenced their intrinsic motivation, affecting their psychological well-being or academic stress. However, no significant association was observed in the case of viral anxiety as a mediator, indicating that viral anxiety did not mediate the association. Conclusion This study highlights the importance of resilience in mediating the relationship between intrinsic motivation and psychological well-being or academic stress. However, viral anxiety was not found to be a mediator in this relationship.