A hollow porous Prussian Blue (HPB)–based nanoplatform was developed for synergistic cancer therapy combining photothermal, photodynamic, and chemotherapy (PTT/PDT/chemo). The HPB core was co-loaded with doxorubicin (DOX) and Radachlorin (RADA) and subsequently coated with poly(acrylic acid) (PAA), yielding the final nanoplatform termed DRHP. Successful PAA coating was confirmed by a shift in zeta potential from +13.64 ± 2.76 mV (HPB) to −32.49 ± 5.02 mV (DRHP). UV–Vis spectroscopy verified dual loading of DOX and RADA, with encapsulation efficiencies of 85.52 ± 2.79% and 83.03 ± 4.13%, respectively. Under 808 nm near-infrared (NIR) laser irradiation, DRHP exhibited rapid and reversible photothermal heating with four stable on/off cycles. Drug release showed a modest increase under acidic conditions (pH 5.5), indicating mild pH-responsive behavior. In B16F10 melanoma and A549 human non-small cell lung cancer cells, DRHP induced pronounced irradiation-dependent cytotoxicity under combined PTT and PDT irradiation while showing negligible dark toxicity. In vivo evaluation using an A549 tumor-bearing mouse model demonstrated significant tumor growth inhibition in the DRHP + laser group without noticeable systemic toxicity. These findings indicate that DRHP functions as a NIR-responsive multimodal nanoplatform with high drug-loading capacity and stable photothermal performance, highlighting its potential as a clinically translatable strategy for synergistic cancer therapy.