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Thymus involution, the age-dependent loss in organ structure and functionality, promotes increased immune dysfunction in humans, causing increased susceptibility to opportunistic infections, peripheral autoimmunity and reduced vaccine efficacy. Despite this, the mechanisms that regulate thymus involution remain incompletely understood. This has resulted in a lack of clinically approved therapies capable of reversing age-associated thymus involution. Here, we identify that thymic epithelial cell (TEC) specific ErbB2 activity determines thymus homeostasis and T cell maturation. In these studies, we use a conditionally regulated bitransgenic mouse model in which a dominant-active ErbB2 transgene is expressed in keratin14 positive TECs following doxycycline administration. We show that increased ErbB2 expression causes rapid onset of thymus atrophy that resembles age-associated involution. Specific changes include destruction of thymic cortico-medullary boundaries, abnormal TEC differentiation, reduced thymus size and cellularity, and abnormal T cell differentiation. Using foetal thymus organ cultures derived from wild type and bitransgenic animals, we confirm that these phenotypes are due to TEC autonomous ErbB2 expression. Finally, we establish that treating aged mice with the clinically approved Erbb2 inhibitor Lapatinib restores thymus function, improves Streptococcus pneumoniae vaccine efficacy, and promotes infection resistance. Overall, these results demonstrate a previously unknown role for ErbB2 in adult thymus homeostasis and suggest the potential translational relevance of ErbB2 inhibition as a means to reduce or reverse age-associated thymus involution.