Delirium is a frequent, serious, and preventable complication in critically ill children. Inflammation has been implicated as a mechanism for the development of delirium. Platelet transfusions may potentiate the body’s pro-inflammatory responses. We hypothesized that receipt of platelets would be associated with delirium development in a pediatric intensive care unit (PICU). We performed a single-center retrospective cohort analysis including children admitted to the PICU between 2014 and 2018 who were transfused platelets within the first 14 days of admission. Data obtained included severity of illness, level of respiratory support, exposure to medications and blood products, as well as daily cognitive status. To account for time-dependent confounding, a marginal structural model (MSM) was constructed to delineate the relationship between platelet transfusion and next-day delirium. MSM demonstrated a 75% increase in the development of next-day delirium after transfusion of platelets (aOR 1.75, 95% CI 1.03–2.97). For every 1 cc/kg of platelet transfused, odds of next-day delirium increased by 9% (odds ratio 1.09, 95% CI 1.03–1.51). We reported an independent association between platelet transfusion and next-day delirium/coma after accounting for time-dependent confounders, with a dose–response effect. Minimizing platelet transfusions as much as clinically feasible may decrease delirium risk in critically ill children.