This comprehensive review investigates the intricate interplay between stress, COVID-19, and trauma, unraveling their interconnected impact on health outcomes. In the contemporary landscape, stressors have multiplied, encompassing daily challenges and global crises. The COVID-19 pandemic, a global disruptor, adds a unique layer to the stress narrative, serving both as a stressor and a source of trauma. Trauma, whether pandemic-induced or arising from personal experiences, leaves a lasting imprint on mental and physical well-being. Exploring the neurobiological tapestry of stress, COVID-19, and trauma sheds light on the underlying mechanisms, revealing their synergistic effects. The intricate dance between the central nervous system, hormonal responses, and the immune system provides a nuanced understanding of health outcomes in the face of this interconnected nexus. This review also addresses health disparities, emphasizing the disproportionate burden borne by vulnerable populations. Social determinants of health play a crucial role in shaping the impact of stress, COVID-19, and trauma on different communities, underscoring the need for targeted interventions Despite the challenges posed by this nexus, individuals and societies exhibit resilience. Effective coping mechanisms, both at individual and societal levels, are explored to provide insights into mitigating the negative health outcomes associated with stress, COVID-19, and trauma.