A novel strategy was designed and developed based of horseradish peroxidase (HRP)-mediated crosslinking of tyramine-functionalized starch (Tyr-St), tannic acid (TA) and phenolated-magnetic nanoparticles (FeO-PhOH NPs), and simultaneous loading of doxorubicin hydrochloride (Dox) to afford a pH-responsive magnetic hydrogel-based drug delivery system (DDS) for synergistic in vitro chemo/hyperthermia therapy of human breast cancer (MCF-7) cells. The developed St-g-PTA/FeO magnetic hydrogel showed porous micro-structure with saturation magnetization (δ) value of 19.2 emu g for FeO NPs content of ∼7.4 wt%. The pore sizes of the St-g-PTA/FeO hydrogel was calculated to be 2400 ± 200 nm. In vitro drug release experiments exhibited the developed DDS has pH-dependent drug release behavior, while at physiological pH (7.4) released only 30 % of the loaded drug after 100 h. Human serum albumin (HSA) adsorption capacities of the synthesized St/FeO and St-g-PTA/FeO magnetic hydrogels were obtained as 86 ± 2.2 and 77 ± 1.9 μgmg, respectively. The well-known MTT-assay approved the cytocompatibility of the developed St-g-PTA/FeO hydrogel, while the Dox-loaded system exhibited higher anti-cancer activity than those of the free Dox as verified by MTT-assay, and optical as well as florescent microscopies imaging. The synergistic chemo/hyperthermia therapy effect was also verified for the developed St-g-PTA/FeO-Dox via hot water approach.