Healthcare workers are highly regarded for their compassion, dedication, and composure. However, COVID-19 created unprecedented demands that rendered healthcare workers vulnerable to increased burnout, anxiety, and depression. This cross-sectional study assessed the psychosocial impact of COVID-19 on U.S. healthcare frontliners using a 38-item online survey administered by Reaction Data between September and December 2020. The survey included five validated scales to assess self-reported burnout (Maslach Summative Burnout Scale), anxiety (GAD-7), depression (PHQ-2), resilience (Brief Resilience Coping Scale), and self-efficacy (New Self-Efficacy Scale-8). We used regression to assess the relationships between demographic variables and the psychosocial scales index scores and found that COVID-19 amplified preexisting burnout (54.8%), anxiety (138.5%), and depression (166.7%), and reduced resilience (5.70%) and self-efficacy (6.5%) among 557 respondents (52.6% male, 47.5% female). High patient volume, extended work hours, staff shortages, and lack of personal protective equipment (PPE) and resources fueled burnout, anxiety, and depression. Respondents were anxious about the indefinite duration of the pandemic/uncertain return to normal (54.8%), were anxious of infecting family (48.3%), and felt conflicted about protecting themselves versus fulfilling their duty to patients (44.3%). Respondents derived strength from their capacity to perform well in tough times (74.15%), emotional support from family/friends (67.2%), and time off work (62.8%). Strategies to promote emotional well-being and job satisfaction can focus on multilevel resilience, safety, and social connectedness.