Introduction The inability of many therapeutic molecules to cross the blood–brain barrier (BBB) combined with poor penetration into tumor tissue leads to difficult challenges for treatment of brain tumors. In order to settle these hurdles, we developed a novel multifunctional targeting carrier which enables drugs to transport across the BBB and targets brain tumor tissues. Methods In the multifunctional targeting liposomes, the natural compound resveratrol (RES) was incorporated into the lipid bilayer membranes of liposomes, while p-aminophenyl-α-D-manno-pyranoside (MAN) and wheat germ agglutinin (WGA) were conjugated to the liposomal surface. Epirubicin (EPI) as an anticancer drug was then loaded into liposomes. Then, liposomes were characterized by evaluation on particle size, zeta potential and apparent morphology. The epirubicin plus resveratrol liposomes modified with WGA and MAN were applied to glioma cells and BBB model in vitro and C6 glioma-bearing rats in vivo. Results The multifunctional targeting liposomes were round shaped with a smooth surface and uniform particle size. In consideration of the SRB results, the multifunctional targeting liposomes indicated a significant inhibitory effect, suggesting that MAN plus WGA generated robust drug delivery effects into the brain tumor cells. The glioma cells after administering epirubicin plus resveratrol liposomes modified with WGA and MAN displayed the most significant uptake and apoptosis conducted by flow cytometry. In the multifunctional targeting effects assay, the epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited the strongest effects of crossing the BBB and then targeting brain tumor cells. In tumor-bearing rats after applying multifunctional targeting liposomes, the median survival time was evidently observed as being markedly longer than other controls. Conclusion The epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited strong ability to improve epirubicin and resveratrol transporting across the BBB and therapeutic effect on brain glioma, showing multifunctional targeting capability.