Background: Acute aortic dissection (AD) is a lethal cardiovascular disease with severe inflammatory complications. Considering the proinflammatory properties of plasma mitochondrial DNA (mtDNA), we postulate that plasma mtDNA from activated platelets may be responsible for post-acute AD inflammatory responses. Methods: We consecutively enrolled 68 patients with acute AD as well as matched hypertensive and healthy participants. Blood samples were collected on admission for blood routine tests, mtDNA assay, and inflammatory cytokine analysis. A computed tomography scan was used to evaluate the extent of dissections. Results: Our results demonstrate that plasma mtDNA, platelet activation, and inflammatory levels were remarkably higher in acute AD patients than in hypertensive or healthy participants. These parameters were also higher in the Stanford A group than in the Stanford B group (p < 0.05). Bivariate correlation analysis demonstrated positive associations between mtDNA and inflammatory levels (tumor necrosis factor-α: r = 0.577; interleukin-6: r = 0.632), mtDNA and platelet activation (r = 0.642), and platelet activation and the extent of dissection (r = 0.635). Conclusion: Our study suggests that acute AD-induced tunica media exposure causes platelet activation, which leads to the initiation of inflammatory responses via the release of mtDNA into the circulation. Our study provides a novel fundamental basis and a potential therapeutic target for the prevention and treatment of post-AD inflammatory responses.