Despite evidence-based guidelines to inform platelet transfusion practice, unnecessary platelet transfusion persists. We performed a multicentre retrospective analysis of adults admitted to general medicine, subspecialty medicine and critical care from 1 January 2017 to 30 June 2022. Platelet transfusion guideline compliance was defined as platelet transfusion below 100 × 10⁹/L for neurosurgical, cardiac surgery or extracorporeal membrane oxygenation indications, below 50 × 10⁹/L for invasive procedures, bleeding or therapeutic anticoagulation, and below 10 × 10⁹/L if the patient did not have an immune-mediated thrombocytopenia. We analysed 821 950 patient admissions at 22 hospital sites, identifying 56 825 platelet transfusion events. Overall, 13 199 (23.2%) platelet transfusion events were guideline-non-compliant. High rates of non-compliant transfusions were observed in the context of anti-platelet therapy (n = 1515, 48.5% non-compliant), cardiac surgery (n = 1935, 49.7%), invasive procedures (n = 4648, 29.2%), immune-mediated thrombocytopenia (n = 596, 32.9%) and primary prophylaxis (n = 7370, 47.2%). After adjusting for physician characteristics, there was a lower risk of guideline-non-compliant platelet transfusions at academic than at community hospitals (odds ratio [OR] 0.768, 95% confidence interval [CI] 0.678–0.871, p < 0.001). Physician specialty, but not physician gender or years in practice, influenced guideline compliance. These findings underscore the need for targeted intervention to optimize platelet transfusion practices, minimize avoidable transfusion reactions, reduce costs and mitigate platelet shortages.