In the present work, we implemented a computational framework of in vivo gold nanorod (GNR)-enhanced photothermal therapy (PTT) for tumor treatment. The temperature-dependent thermophysical properties of biological tissue and the optical properties of both GNRs and the biological media were included. The latter were modulated during the treatment simulation to account for their variation, from the native to the coagulated state. The contribution of tissue injury-dependent blood perfusion was also considered. The developed model allowed for the estimation of temperature distribution during the photothermal procedure at different procedural settings and amounts of GNRs embedded in the tumor region (i.e., 12.5 μg, 25 μg, and 50 μg). Furthermore, the influence of GNRs on thermal injury, estimated with different damage models, was assessed. The inclusion of GNRs in the tumor entailed an increment of maximum tissue temperature, and faster heating kinetics, as witnessed by the lower time needed to reach complete thermal damage at the tumor center. The percentage of tumor thermal damage evaluated at the end of the simulated treatment was 48%, 69%, and 90%, for PTT in the presence of 12.5 μg, 25 μg, and 50 μg of GNRs, respectively.Clinical Relevance-This establishes that simulation-based tools, modeling the tissue properties variation during the photothermal treatment, can serve as promising preplanning platforms for nanoparticle-assisted light therapies.