Pediatric head injury is the most common cause of death among US children. Depending on the brain injury, the literature offers conflicting evidence for an increased or decreased vulnerability in the toddler compared to the infant. We combined clinical data of head injuries in infants and toddlers with anthropomorphic dummy studies, animal experiments and finite element model simulations to systematically identify differences in vulnerability to traumatic head injury in infants and toddlers. We found that among infants and toddlers hospitalized for accidental head trauma, significantly more infants sustained a skull fracture compared to toddlers whereas toddlers presented with neurological impairment more frequently than infants, demonstrating unique injuries across age. For head contact events, anthropomorphic dummy studies of falls < 3 feet revealed larger head rotational acceleration and smaller impact duration in the toddler than the infant for the same drop heights and contact surfaces, suggesting that although a thicker, fused skull may protect the toddler from skull fracture, it absorbs less energy on impact, contributing to large head accelerations that might produce more frequent neurological impairment. Non-impact rapid rotations in an animal model demonstrate that moderate rotations in the toddler piglet produce similar subarachnoid hemorrhage and axonal injury severity compared to acceleration-matched rotations in the infant piglet. Furthermore, mild rotations in the toddler piglet produced significantly less severe injuries compared to mass-scaled rotations in the infant. These experimental findings refute the concept that age-dependent injury responses depend solely on mass scaling effects. To compare infant and toddler tissue strain thresholds, we used the measured loads and associated pathology from the animal studies and a 3D finite element model of the piglet head. We found that the tissue strain threshold required for axonal injury was 3 times higher in the toddler piglet compared to the infant. In summary, enhanced vulnerability of the infant to skull fracture and brain injury compared to the toddler is attributed to differences in brain size, skull thickness, material properties, and injury strains thresholds. These studies provide a rationale for the development of age-specific injury prevention methods to reduce head injuries in infants and toddlers.