ErbB2 overexpression identifies a subclass of breast cancer as ErbB2-positive that is frequently associated with poor prognosis. Current ErbB2-targeted therapies have profoundly improved patient outcomes, but mutations occurring in ErbB2 have been shown to confer drug resistance. Induction of ErbB2 degradation was proposed as an intriguing strategy to battle with ErbB2-positive breast cancer and reduced mutation-incurred drug resistance. Although multiple HSP90 inhibitors have been demonstrated to effectively trigger ErbB2 degradation, none succeeded in the clinical evaluations. To develop novel ErbB2-targeting strategies, we investigated the endocytic degradation and reversible ubiquitylation of ErbB2 in breast cancer. In this study, we reveal that HSP90 inhibition leads to efficient ubiquitylation and endocytic degradation of ErbB2 through the canonical endo-lysosomal route. USP2 associates with internalized ErbB2 and prevents its lysosomal sorting and degradation via exerting deubiquitylase activity. Accordingly, the USP2 inhibitor ML364 is capable of inducing ErbB2 ubiquitylation and accelerating its turnover. ML364 potentiates the pro-degradation effects of HSP90 inhibitors on ErbB2 and hence sensitizes ErbB2-positive breast cancer cells to HSP90 inhibition. The combination of USP2 and HSP90 inhibitors effectively restrains ErbB2-positive breast cancer xenograft growth in vivo. Based on these observations, we conclude that USP2 safeguards ErbB2 surface levels by antagonizing its ubiquitylation-mediated endocytic degradation, which can be exploited to design novel therapeutic strategies against ErbB2-driven malignancies as combinatorial treatment with HSP90 inhibitors.