Background: Burnout during residency may be a function of intense professional demands and poor work/life balance. With the onset of the COVID-19 pandemic, NYC hospital systems were quickly overwhelmed, and trainees were required to perform beyond the usual clinical duties with less supervision and limited education. Objective: The present longitudinal study examined the effects of COVID-19 caseload over time on burnout experienced by resident physicians and explored the effects of demographic characteristics and organizational and personal factors as predictors of burnout severity. Methods: This study employed a prospective design with repeated measurements from April 2020 to June 2020. Participants were surveyed about their well-being every 5 days. Predictors included caseload, sociodemographic variables, self-efficacy, hospital support, perceived professional development, meaning in work, and postgraduate training level. Results: In total, 54 resident physicians were recruited, of whom 50% reported burnout on initial assessment. Periods of higher caseload were associated with higher burnout. PGY-3 residents reported more burnout initially but appeared to recover faster compared to PGY-1 residents. Examined individually, higher self-efficacy, professional development, meaningful work, and hospital support were associated with lower burnout. When all four predictors were entered simultaneously, only self-efficacy was associated with burnout. However, professional development, meaningful work, and hospital support were associated with self-efficacy. Conclusion: Burnout among residency is prevalent and may have implications for burnout during later stages of a physician’s career. Self-efficacy is associated with lower burnout and interventions to increase self-efficacy and the interpersonal factors that promote self-efficacy may improve physician physical and emotional well-being.