Based on aminated β-cyclodextrin (6-NH-β-CD)-grafted FeO and gambogic acid (GA) clathrate complexes, a nanoparticle delivery system was developed with the aim to achieve low irritation, strong targeting, and high bioavailability of a gambogic acid magnetic nanopreparation. 6-NH-β-CD grafted onto FeO MNPs was demonstrated by high-resolution transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, zeta potential, and magnetic measurements. The average particle size of the FeO@NH-β-CD MNPs was 147.4 ± 0.28 nm and the PDI was 0.072 ± 0.013. The encapsulation efficiency, drug loading, zeta potential, and magnetic saturation values of the FeO@NH-β-CD MNPs were 85.71 ± 3.47%, 4.63 ± 0.04%, -29.3 ± 0.42 mV, and 46.68 emu g, respectively. Compared with free GA, the release profile of GA from FeO@NH-β-CD MNPs was characterized by two phases: an initial fast release and a delayed-release phase. The FeO@NH-β-CD MNPs displayed continuously increased cytotoxicity against HL-60 and HepG2 cell lines in 24 h, whereas the carrier FeO@NH-β-CD MNPs showed almost no cytotoxicity, indicating that the release of GA from the nanoparticles had a sustained profile and FeO@NH-β-CD MNPs as a tumor tissue-targeted drug delivery system have great potential. Besides, blood vessel irritation tests suggested that the vascular irritation could be reduced by the use of FeO@NH-β-CD MNPs encapsulation for GA. The and the AUC of the FeO@NH-β-CD@GA MNPs were found to be higher than those for the GA solution by approximately 2.71-fold and 2.42-fold in a pharmacokinetic study, respectively. The better biocompatibility and the combined properties of specific targeting and complexation ability with hydrophobic drugs make the FeO@NH-β-CD MNPs an exciting prospect for the targeted delivery of GA.