In New Zealand, possums (Trichosurus vulpecula) are the main wildlife reservoir for bovine tuberculosis (Tb), which they transmit to livestock. This study investigated oral vaccination with lipid-formulated Mycobacterium bovis BCG and subsequent protection against virulent M. bovis challenge in wild-caught possums. Possums were trapped from the field and either hand-vaccinated and released back into the wild, or acclimatised to captive conditions prior to voluntary uptake of flavoured vaccine. Possums were subsequently exposed to pulmonary challenge with virulent M. bovis, administered either by instillation of a liquid suspension as an intra-tracheal challenge (field animals) or in micro-droplets as an aerosol (captive animals). Field studies indicated that the relative risk of death in wild possums due to Tb was 2.4 times greater in control compared with orally-vaccinated possums, with the vaccine conferring protection to possums in both good and poor body condition. Laboratory studies indicated that oral vaccination conferred protection in cage-acclimatised possums, with >3log₁₀ reduction in lung bacterial burdens among vaccinated animals. This study provides evidence that lipid-formulated BCG oral vaccine can provide significant protection to possums in field as well as laboratory conditions, which may favour the use of this formulation as a delivery method for controlling wildlife Tb.