Supramolecular host–guest complexes have the ability to prolong the circulation time, and promote the efficiency of hydrophobic drugs. Therefore, in this project we immobilized cyclodextrin (CD), as a host molecule for tamoxifen (TMX), to mitoxantrone (MTX) conjugated magnetic nanoparticles for simultaneous delivery of anti-cancer drugs toward folate-positive cancer cells. FESEM photography of the magnetic multi-drugs carrier confirmed a hollow circular structure for self-assembled layers of cyclodextrin conjugated to MNPs with average size about 95 nm. Drugs release from supramolecular magnetic nanoparticles (with 86.08% of TMX encapsulation and 60.3% of MTX loading) revealed that protease enzymes can enhance the MTX liberation at pH 5, but don't have any noticeable effect on liberation of TMX at both pH conditions. Also, the simultaneous presence of two drugs onto MNPs induced cytotoxicity in two cancer cell lines, MCF-7 and A549, which is different from the impact of each one of drugs alone. Therefore, we believe that this simultaneous carrier could enhance the efficiency of TMX and MTX anti-cancer drugs and be useful for the intended applications, due to hydrophilicity of supramolecular host–guest complexes and its inherent ability to target folate receptors, simultaneously.