Myasthenia gravis (MG) is an autoimmune disorder that disrupts neuromuscular junction function through autoantibodies. Platelets are emerging as key players in the pathogenesis of MG, bridging innate and adaptive immunity. We analyze platelet transcriptome signatures and their interactions with the immune system in AChR+ immunotherapy-naïve MG (nMG) patients using bulk and single-cell RNA sequencing on peripheral blood mononuclear cells (PBMC). nMG patients exhibit upregulation of genes related to activation, inflammation, and cytoskeletal regulation. Increased platelet count, activation, altered morphology, enhanced CD62P expression, and elevated plasma CD40L levels are observed in PBMCs, which diminish with minimal clinical status (MMS). Functionally, platelets show heightened interactions with leukocytes, forming aggregates that correlate with disease severity. These features return to baseline after intravenous immunoglobulin or prolonged immunosuppressive therapy. This study underscores platelet activation's critical role in MG and supports platelet-targeted therapy.© 2025. The Author(s).