One of the chemotherapeutic drugs in the first-line treatment of osteosarcoma is doxorubicin (dox). However, its anticancer efficacy is limited by the overexpression of the multidrug efflux transporter P-glycoprotein (Pgp) which extrudes doxorubicin, disrupts drug accumulation and thus hinders the cytotoxic activity of dox The drug extrusion activity of Pgp is enhanced by the presence of cholesterol within the plasma membrane. Pgp expression is up-regulated by multiple transcription factors including hypoxia inducible factor-1α (HIF-1α). Decreasing Pgp expression and drug efflux activity may enhance the efficacy of doxorubicin against drug resistant osteosarcoma. To achieve this goal, we treated two human dox-sensitive cell lines (U-2OS and Saos-2), and their sublines displaying increasing Pgp levels and dox resistance, with a non-toxic dose of atorvastatin. This statin was able to decrease the biosynthesis of farnesyl pyrophosphate (FPP) and cholesterol, two key metabolites that were markedly increased in drug resistant sublines. By reducing the FPP levels, atorvastatin decreased the Ras/ERK1/2/HIF-1α axis and down-regulated Pgp expression. Moreover, by decreasing cholesterol biosynthesis atorvastatin increased the levels of low density lipoprotein receptor (LDLR), that was also progressively increased in the dox-resistant sublines. Taking advantage of this findings, we treated dox-resistant osteosarcoma with atorvastatin followed by treatment with dox encapsulated in liposomes decorated with an LDLR-binding peptide, hence facilitating binding to, and endocytosis via LDLR. This treatment strategy induced high retention of dox in dox-resistant cells, reduced cell viability in vitro and displayed growth inhibition of dox-resistance in mouse xenograft model. Hence, we propose the combination of statins plus LDL-decorated liposomal dox as a novel treatment strategy for Pgp-expressing multidrug resistant osteosarcomas.