Trauma represents a significant global health issue, often resulting in devastating and long-lasting effects on the body throughout a patient's life. Organ inflammation and dysfunction caused by trauma present additional challenges for clinicians. Therefore, understanding the cellular and molecular mechanisms of post-trauma systemic inflammation and organ dysfunction is essential for improving the management of trauma. This review aims to summarize current updates on the findings that explore different mechanisms of trauma-induced inflammation and organ dysfunction, highlighting the recent understanding of the vital roles of damage-associated molecular patterns, trauma-induced cell death, organ–organ cross-talk pathways, and the gut microbiota in the development and progression of post-traumatic systemic inflammation. We also discuss new approaches that can potentially guide further investigations of trauma diagnosis, treatment, and prognosis.