Low-intensity focused ultrasound (LIFU) is a new noninvasive brain stimulation technique where ultrasound is applied with low frequency and intensity to focus at a target region within the brain in order to exhibit or inhibit neuronal activity. In applying LIFU to the human brain, the skull is the main barrier due to its well-known high anisotropic mechanical properties which will affect the ultrasound focusing thereby affecting the neuromodulation or brain stimulation. This study aims at investigating the influence of the anisotropic mechanical properties of the skull on ultrasound propagation and focusing in LIFU. In this study, we used 2D finite element (FE) head models incorporating the isotropic and anisotropic properties of the skull. Three kinds of stresses were examined and shown within the skull: namely the normal stress in the direction of wave propagation ([Formula: see text]-stress), normal stress in the transverse direction to the wave propagation ([Formula: see text]-stress), and shear stress. Our analysis show that although most of the pressure that reaches to the brain is due to the longitudinal wave propagation through the skull, the stress in the transverse direction to the wave propagation direction ([Formula: see text]-stress) has the main influence on the pressure profile inside the brain. The results also show that the anisotropic properties of the skull broaden the focal size about 19% and 13% in the longitudinal and transverse directions, respectively more than the case of considering the isotropic properties in the realistic 2D FE head model. The results indicate the importance of considering the anisotropic properties of the skull in practicing LIFU to achieve accurate targeting within the brain.