This paper is motivated by possible medical applications of focused ultrasound in the minimally invasive treatment of a variety of musculoskeletal disorders that are responsive to thermal treatment. A model-based analysis of the interaction of high-intensity focused ultrasound with biological materials is carried out in an effort to predict the path of the sound waves and the temperature field in the focal region. A finite-element-based general purpose code called PZFlex is used to determine the effects of nonlinearity and geometrical complexity of biological structures. It was found that at frequencies of interest in therapeutic applications, the nonlinear effects are usually negligible and the geometrical complexities can be handled through a substructuring procedure. An approximate analytical method with acceptable accuracy is developed as an alternative to the purely numerical approach used in PZFlex. The mechanical and thermal effects in two-layered fluid material systems induced by high-frequency focused ultrasound are calculated through this analytical method. The results are compared with those obtained using PZFlex as a benchmark.