Motorcyclists account for 23% of global road traffic deaths and over half of fatalities in countries where motorcycles are the dominant means of transport. Wearing a helmet can reduce the risk of head injury by as much as 69% and death by 42%; however, both child and adult helmet use are low in many countries where motorcycles are a primary mode of transportation. In response to the need to increase helmet use by all drivers and their passengers, the Global Helmet Vaccine Initiative (GHVI) was established to increase helmet use in three countries where a substantial portion of road users are motorcyclists and where helmet use is low. The GHVI approach includes five strategies to increase helmet use: targeted programs, helmet access, public awareness, institutional policies, and monitoring and evaluation. The application of GHVI to Vietnam, Cambodia, and Uganda resulted in four key lessons learned. First, motorcyclists are more likely to wear helmets when helmet use is mandated and enforced. Second, programs targeted to at-risk motorcyclists, such as child passengers, combined with improved awareness among the broader population, can result in greater public support needed to encourage action by decision-makers. Third, for broad population-level change, using multiple strategies in tandem can be more effective than using a single strategy alone. Lastly, the successful expansion of GHVI into Cambodia and Uganda has been hindered by the lack of helmet accessibility and affordability, a core component contributing to its success in Vietnam. This paper will review the development of the GHVI five-pillar approach in Vietnam, subsequent efforts to implement the model in Cambodia and Uganda, and lessons learned from these applications to protect motorcycle drivers and their adult and child passengers from injury.