Background: Physician burnout is a serious issue associated with physician attrition, mental and physical problems, and medical errors. Objectives: This study aimed to investigate the prevalence of overall burnout among interns-residents and general physicians (GPs)-specialists during the coronavirus disease 2019 (COVID-19) pandemic in Iran. Methods: This cross-sectional study was conducted among 220 interns-residents and 212 GPs-specialists in university-affiliated hospitals and clinics in Shiraz, Iran. A convenience sampling method was used to recruit the samples, and the data were gathered using Maslach Burnout Inventory that was previously validated for the Persian language. We used covariance analysis and multiple logistic regression to analyze the data. Results: The mean age of participants was 31.44 (ranged 21-62) years. Multiple logistic regression for GPs-specialists showed that working in COVID-19 wards during June-July (OR = 13.93, P = 0.01, CI: 3.61 - 53.51) was associated with increased odds of overall burnout. Moreover, older age among GPs-specialists was associated with decreased odds of overall burnout (OR = 0.94, P = 0.01, CI: 0.90 - 0.98). On the other hand, the odds of overall burnout among interns-residents was not significantly different between various periods (P = 0.94). Furthermore, age (OR = 0.24, P = 0.01, CI: 0.04 - 0.47) and being married (OR = 0.31, P = 0.02, CI: 0.12 - 0.81) were positively associated with decreased odds of overall burnout among interns-residents. Conclusions: This study revealed that the risk of professional burnout among specialists and GPs increased over time during the COVID-19 pandemic. Moreover, older physicians had a lower risk of burnout. Despite the disagreements regarding the association between burnout and the duration of exposure to patients during epidemics, the findings of this study have the potential to remind policymakers of the importance of the issue among physicians during pandemics to taking appropriate action to prevent this phenomenon.