In this study, we developed a novel strategy for in situ encapsulation of hydrophobic drugs such as curcumin into the magnetite-mesoporous silica nanocomposites with a core-shell structure. In the proposed method, a modified reverse microemulsion system was used for silica formation on the surface of curcumin-loaded Fe3O4 nanoparticles (Cur@Fe3O4 NPs) to render mesoporous silica-coated Cur@Fe3O4 NPs (SiO2/Cur@Fe3O4 NPs). The prepared SiO2/Cur@Fe3O4 NPs with a core-shell structure had a spherical shape with a mean particle size less than 100 nm. The heating efficacy of the prepared nanocomposites was examined for application in magnetic hyperthermia therapy by exposing them to different biological safe alternating magnetic fields. The maximum specific absorption rate (SAR) obtained by the prepared sample, was found to be 22.11 WgFe3O4−1at the magnetic field intensity of 28 kA m−1 and frequency of 120 kHz.. Also, the prepared nanocomposites exhibited a pH-responsive drug release behavior. The in vitro drug release studies showed that, only 8.9% of curcumin was releasedwas from SiO2/Cur@Fe3O4 NPs at pH 7.4, while about 40% of drug was released at pH 5.0, after 5 days. Moreover, the in vitro cytotoxicity analysis showed that, by encapsulation of curcumin in the prepared nanocomposites, the cytotoxicity of the drug was significantly increased against breast cancer MCF-7 cells, compared to the free drug, so that, at curcumin concentration of 40 μg mL−1, the viability of MCF-7 cells incubated with free curcumin was 62.0%, whereas by encapsulation of curcumin in SiO2/Cur@Fe3O4 NPs the viability was decreased to 26.7% (Pvalue ≤ 0.005).