Background: Healthcare workers (HCWs) faced numerous job-related hazards during the COVID-19 pandemic outbreak, such as job-related stress and burnout, which are considered to be the paramount burdens. The aim of the present study was to assess the extent of burnout and stress among HCWs during COVID-19 in primary healthcare centers. Methods and Results: This cross-sectional study was conducted at five primary healthcare centers in Port Said governorate (Egypt). The study sample consisted of 250 HCWs (physicians, nurses, pharmacists, paramedical personnel, and administrative staff). Measurement tools included Maslach Burnout Inventory (MDI) and Perceived Stress Scale (PSS). Regarding degree of burnout, the current study results concluded that, two-thirds of HCWs had high occupational exhaustion, around three-quarters had high depersonalization, and the majority of them had low PA assessment. Regarding stress levels, almost half of HCWs had high stress, and more than one-third had moderate stress. There was a statistically significant, positive correlation between degrees of occupational exhaustion, depersonalization, and stress level. Conclusion: This research can inform healthcare leaders and enable them to improve HCWs’ experience by addressing levels of stress and burnout; managers must support staff who provide care and service to decrease the harmful effects of the COVID-19 pandemic.