Due to its high degree of accuracy and non-invasive implementation, pulsed-high intensity focused ultrasound (HIFU) is a promising modality for hyperthermia applications as adjuvant therapy for cancer treatment. However, the relatively small focal region of the HIFU beam could result in prohibitively long treatment times for large targets requiring multiple exposures. In this work, finite element analysis modeling was used to simulate focused ultrasound propagation and the consequent induction of hyperthermia. The accuracy of the simulations was first validated with thermocouple measurements in hydrogel phantoms. More advanced simulations of in vivo applications using single HIFU exposures were then done incorporating complex, multi-layered tissue composition and variable perfusion for an in vivo murine xenograft tumor model. The results of this study describe the development of a preliminary methodology for optimizing spatial application of hyperthermia, through the evaluation of different HIFU exposures. These types of simulations, and their validations in vivo, may help minimize treatment durations for pulsed-HIFU induced hyperthermia and facilitate the translation of these exposures into the clinic.