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Thermosensitive liposomal (TSL) drug delivery with intravascular release under hyperthermia is a promising approach for chemotherapy of solid tumors, where the hyperthermia schedule strongly influences delivery efficacy. This study uses mathematical modeling to evaluate these effects. A compartmental modeling approach was used to simulate TSL-encapsulated doxorubicin (DOX) delivery. The model was calibrated and validated against published in vivo data from murine tumor models. Key variables included hyperthermia timing relative to TSL-DOX administration (0-60 min), duration (15-90 min), and heating pattern (continuous vs. fractional). Tumor cells exhibiting multidrug resistance (MDR), based on uptake characteristics of non-small cell lung cancer (NSCLC) and breast cancer cells, were modeled by varying cellular efflux rates. Initiating hyperthermia at peak plasma TSL levels increased the maximum intracellular DOX concentration by up to twofold compared with a 60-min delay. Tumor models characterized by NSCLC-like uptake were less responsive to prolonged hyperthermia than MCF-7 and MDA-468 breast cancer cells, showing minimal additional intracellular accumulation beyond 60 min. Low-MDR tumor models exhibited greater hyperthermia-enhanced uptake than high-MDR models. Prolonged hyperthermia increased systemic exposure to free DOX; however, the relative enhancement in tumor exposure exceeded that in systemic plasma. Continuous hyperthermia yielded a 20% higher intracellular DOX concentration after 60 min compared with a fractional schedule (4 × 15 min with 15-min cool-down intervals). For optimal delivery, hyperthermia in the stationary phase is most effective when synchronized with peak plasma TSL-DOX levels. Hyperthermia duration may require cancer-type-specific adjustment. These findings provide a mechanistic basis to inform hyperthermia protocol design.