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Platelet transfusions are essential in the management of thrombocytopenia, bleeding disorders, and hematologic malignancies. With cannabis use rising worldwide, its impact on donor platelet quality and transfusion efficacy remains poorly understood. This study investigated the effects of cannabis joint extracts (CJE) on platelet activation, pro-coagulant phenotype, mitochondrial function, and cytokine/chemokine release, with implications for transfusion safety. Human platelets were exposed in vitro to increasing concentrations of two CJE with distinct cannabinoid profiles: Orchid (O-CJE, THC 10.4%, CBD 14.7%) and QCGold (G-CJE, THC 25.5%, CBD 0.04%). Platelet activation (CD62P, Annexin V), mitochondrial depolarization, ATP levels, aggregation responses, and cytokine secretion (CCL3, PF4) were assessed. RBC lysate experiments were performed to assess the role of hemolysis. The involvement of CB1 and CB2 receptors was tested using specific antagonists, and activation of p38 MAPK and NF-κB pathways was evaluated. Functional effects of platelet supernatants were examined on EA.hy926 endothelial cells. CJE exposure induced dose-dependent platelet activation, characterized by increased CD62P expression, Annexin V binding, mitochondrial depolarization, and ATP depletion, consistent with metabolic stress. Platelet aggregation in response to ADP, collagen, and arachidonic acid was impaired, suggesting a pre-activated or refractory phenotype. RBC lysate did not reproduce the observed effects, indicating hemolysis is unlikely to be the underlying mechanism. CBR1 and CBR2 antagonists did not attenuate platelet activation, while signaling analysis revealed activation of p38 MAPK and NF-κB pathways. Exploratory proteomics indicated modulation of proteins involved in angiogenesis, cytoskeletal organization, and stress responses. Elevated plasma levels of CCL3 and PF4 and endothelial activation (IL-6 secretion, CD54, CD62P, CD62E expression) further suggested a pro-inflammatory environment. Cannabis exposure can alter platelet phenotype and signaling under in vitro conditions, potentially affecting platelet function and interactions with the vascular endothelium. However, these findings require confirmation in vivo to determine their clinical relevance. Future studies should aim to establish exposure thresholds and clarify whether cannabis use has implications for transfusion safety, given potential risks of reduced efficacy or increased thrombotic complications in recipients.