Globally, the COVID-19 pandemic has presented serious mental health challenges for healthcare professionals. This study investigated the mental health, mental fatigue, quality of life, and stigma of social discrimination among healthcare workers in the United Arab Emirates (UAE) during the COVID-19 pandemic. A correlational, cross-sectional, multi-centric design was employed to collect data from 1383 healthcare workers across various healthcare settings. Participants were recruited using combined cluster and purposive sampling techniques. Standardized questionnaires, including the COVID-19 Pandemic Mental Health Questionnaire (CoPaQ), the Mental Fatigue Scale (MFS), the Social Discrimination Scale-Stigma Subscale (SDS), and the WHO Quality of Life Questionnaire-Brief (WHOQOL-BREF), were administered to assess the study variables. The results indicated significant mental health impacts, with high average scores for post-traumatic stress disorder (PTSD) (9.37 ± 6.74) and positive coping by inner strengths (17.63 ± 5.72). Mental fatigue was prevalent (8.15 ± 8.62), and stigma of social discrimination scored notably (23.83 ± 7.46). Quality of life was the highest in the social domain (65.38 ± 24.58). Significant correlations were observed between mental health subscales, mental fatigue, and quality of life domains. These findings highlight the critical need for targeted mental health support programs, improved social support networks, and personalized interventions to mitigate the mental health challenges faced by healthcare workers. Healthcare organizations can guarantee a resilient workforce that can handle future health crises by giving mental health resources and support systems top priority.