Background <p>Sepsis and heatstroke, although arising from microbial infection or environmental heat exposure, converge upon similar pathophysiological systemic inflammatory responses that include immune dysregulation, mitochondrial dysfunction, endothelial injury, and multiorgan failure. Despite this overlap, important mechanistic differences, especially in the initiating triggers and immune response dynamics, distinguish their clinical manifestations and therapeutic strategies.</p> Findings <p>Sepsis is initiated by pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors, whereas heatstroke stems from the release of damage-associated molecular patterns (DAMPs) in response to thermal injury. Both syndromes disrupt mitochondrial integrity, leading to impaired oxidative phosphorylation, an excess production of reactive oxygen species (ROS), and the release of mitochondrial DNA and cytochrome C, which further amplify inflammation and promote cell death. Leukocytes undergo diverse forms of death—including apoptosis, necroptosis, pyroptosis, and ferroptosis—compounding immune dysfunction. Coagulopathy and disseminated intravascular coagulation are prevalent in both conditions, driven by endothelial injury, platelet activation, and NET formation, although microbial toxins intensify this response in sepsis.</p> Conclusions <p>This review synthesizes current evidence to delineate the converging and diverging pathways of sepsis and heatstroke, with a focus on mitochondrial injury, immune paralysis, and thromboinflammation. We also explore emerging biomarkers and novel therapeutic targets, including mitochondrial stabilizers and modulators of cell death. A comprehensive understanding of these mechanisms can inform precision medicine strategies and improve outcomes in both syndromes.</p>