Objective To develop a head ultrasound (HUS) screening protocol for infants born <32 weeks gestational age (GA) that accurately identifies severe brain injury (SBI) while minimizing resource use. Study design Retrospective cohort study of infants born <32 weeks GA, admitted to a level 3 neonatal intensive care unit between 2011 and 2017. Timing and results of each HUS were reviewed. SBI was defined as intraventricular hemorrhage grade ≥3 and/or periventricular leukomalacia. Logistic regression models were used to identify risk factors and evaluate the predictive value of HUS at different time points during hospitalization. Results Of 651 included infants, 71 (11%) developed SBI. Risk factors for SBI were GA at birth <29 weeks (adjusted odds ratio (aOR) 2.87, 95% confidence interval (CI) 1.50–5.48), vasopressors on admission (aOR 3.08, 95%CI 1.38–6.88) and mechanical ventilation on admission (aOR 2.50, 95%CI 1.33–4.68). Infants were classified into three risk groups based on these risk factors, and combinations of 1–5 HUS time points were evaluated to determine the optimal number and timing of HUS for each group. The optimal number of screening HUS ranged from 1 for low-risk to 2 for high-risk infants. Adopting a screening protocol using the number and timing of HUS optimized by risk group could reduce the total number of HUS performed by 40% and the median number of HUS per infant from 3 (IQR 2–4) to 2 (IQR 1–3) (p < .01). Conclusions Implementation of a risk factor-based HUS screening protocol can help reduce resource use while maintaining high sensitivity for detecting SBI.