The standard breast cancer therapy still faces major challenges due to non-specific tumor distribution and occurrence of dose-limiting adverse side-effects. Nanomedicine constitutes an appealing approach to improve the therapeutic index of different anti-cancer drugs. Given their biocompatibility, low-cost manufacture and easy surface modification, lipid nanoparticles, such as solid lipid nanoparticles (SLN), have a great potential for drug delivery in cancer therapy. In this work, SLN entrapping the antineoplastic drug Mitoxantrone (Mito) were developed and functionalized with Disteroylphosphatidylethanolamine-poly(ethylene glycol)-folic acid (DSPE-PEG-FA) ligand to improve blood circulation and tumor selectivity and limit the drug systemic side-effects. Nanoparticles presented adequate size and size distribution for intravenous injection and were stable for at least 6 months. Additionally, their hemocompatibility was demonstrated. Moreover, functionalized nanoparticles were able to improve the anti-cancer effect of the free drug, as assessed by the values of IC and the apoptotic effects in MCF-7 cells. Moreover, an enhanced cellular internalization of the functionalized SLN was demonstrated by confocal microscopy and flow cytometry studies. Finally, the cellular uptake of the SLN was found to occur via macropinocytosis and clathrin-mediated endocytosis, suggesting the involvement of (folate receptor) (FR)-mediated endocytosis. Overall these findings highlight that the developed SLN are efficient nanocarriers for the selective delivery of Mito to breast cancer cells.