Abstract <p>Survival rates of preterm infants have been steadily increasing over the last few decades. This has drawn long-term outcomes in this population to the forefront of scientific attention. Caffeine is a pharmacological agent that is available to neonatologists in the treatment of apnoea of prematurity. Its use for this condition has been well researched; however, less focus has been directed towards its neuroprotective capabilities. Long-term follow-up from the landmark ‘Caffeine Therapy for Apnoea of Prematurity’ trial suggested that caffeine may confer benefits in neurodevelopmental outcomes. The indirect ways in which caffeine could confer these benefits have been extensively discussed; however, the direct molecular mechanisms by which this is achieved are poorly understood. This article reviews the putative mechanisms through which caffeine acts as a neuroprotectant in the preterm infant. Caffeine may directly confer neuroprotective benefits through altering white matter structures, reducing inflammation, preventing cell death and conferring neuromodulatory benefits. With the rise in preterm birth and the need for effective neuroprotective therapies, caffeine’s multifaceted mechanisms offer promising avenues for future research and clinical application.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>This article adds to the existing literature by which it: reviews the putative mechanisms through which caffeine acts as a neuroprotectant</p> </ItemContent> <ItemContent> <p>hypotheses that caffeine confers neuroprotective benefits through altering white matter structures, reducing inflammation, preventing cell death, and conferring neuromodulatory benefits, and</p> </ItemContent> <ItemContent> <p>consolidates evidence regarding caffeine’s impact on neurodevelopmental outcomes</p> </ItemContent> </UnorderedList></p>