High-risk childhood leukemia has a poor prognosis due to treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success in improving the biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited due to a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor (i.e. CD19, CD20, CD22 or CD38) and methoxy polyethylene glycol (PEG) for targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a “mix-and-match” principle where BsAbs are selected based on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and xenografts that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were not detrimental toward healthy peripheral blood mononuclear cells or hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression and extended overall survival by up to three-fold in patient-derived xenograft models of high-risk childhood leukemia. Our methodology employing BsAbs therefore represent an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia.