ZnS:Mn2+ quantum dots (QDs) Fe3O4 QDs/SiO2/P(NIPAAm-co-AAm) core-shell-shell nanocomposites have been successfully fabricated by free radical polymerization method. The average diameter and LCST of ZnS:Mn2+ QDs Fe3O4 QDs/SiO2/P(NIPAAm-co-AAm) (NIPAAm:AAm=90:10) nanocomposites was about 200 nm and 41.1°. It possessed a strong yellow-orange emission peak centered at 589 nm from the Mn2+ 4T1-6A1 transition and the desired superparamagnetic property at room temperature. The DOX encapsulation efficiency and loading capacity was 88% and 15.3 wt%, respectively. The nanocomposites showed the faster drug release behavior at 43 °C than that at 25 °C in vitro release experiment, and exhibited no significant cytotoxicity against the HeLa, HepG2 and HEK293 cell lines. Red fluorescence was observed in the cytoplasm of HeLa cells, confirming its application for biolabeling. Effective tumor inhibition was realized in vivo without the induction of toxicity in mice. ZnS:Mn2+ (QDs) Fe3O4 QDs/SiO2/P(NIPAAm-co-AAm) nanocomposites showed the red fluorescence in the cytoplasm of HeLa cells, faster drug release behavior at 43 °C than that at 25 °C in vitro, and effective tumor inhibition in vivo, confirming its application for drug delivery.