Transboundary animal diseases including foot-and-mouth disease and haemorrhagic septicaemia remain a major constraint for improving smallholder large ruminant productivity in the Mekong region, producing negative impacts on rural livelihoods and compromising efforts to reduce poverty and food insecurity. The traditional husbandry practices of smallholders largely exclude preventive health measures, increasing risks of disease transmission. Although significant efforts have been made to understand the social aspects of change development in agricultural production, attention to improving the adoption of biosecurity has been limited. This study reviews smallholder biosecurity risk factors identified in the peer-reviewed literature and from field research observations conducted in Cambodia and Laos during 2006-2013, considering these in the context of a change management perspective aimed at improving adoption of biosecurity measures. Motivation for change, resistance to change, knowledge management, cultural dimensions, systems theory and leadership are discussed. Due to geographical, physical and resource variability, the implementation of biosecurity interventions suitable for smallholders is not a 'one size fits all'. Smallholders should be educated in biosecurity principles and empowered to make personal decisions rather than adopt prescribed pre-defined interventions. Biosecurity interventions should be aligned with smallholder farmer motivations, preferably offering clear short-term risk management benefits that elicit interest from smallholders. Linking biosecurity and disease control with improved livestock productivity provides opportunities for sustainable improvements in livelihoods. Participatory research and extension that improves farmer knowledge and practices offers a pathway to elicit sustainable broad-scale social change. However, examples of successes need to be communicated both at the 'evidence-based level' to influence regional policy development and at the village or commune level, with 'champion farmers' and 'cross-visits' used to lead local change. The adoption of applied change management principles to improving regional biosecurity may assist current efforts to control and eradicate transboundary diseases in the Mekong region.