Fluid flow through low-permeable rock masses is dominated by transport through discontinuities such as fractures, faults, and joints present in the rock. These discontinuities are beneficial for some geo-resources such as geothermal, oil and gas reservoir, but detrimental for other applications such as CO2 storage and hazardous waste isolation. Fracture orientation plays a critical role during the design of the geo-resources. Often times, ultrasonic waves are used in the field to locate and characterize the fractures. In this study, the effect of fracture orientation (0° to 90°) on ultrasonic wave signatures was investigated by conducting a series of experiments on a granite rock with a longitudinal fracture under confining pressures of 15, 30, and 45 MPa. Ultrasonic wave signatures during the experiment were collected using the ultrasonic transducers embedded in the core holders that were attached to the two ends of the specimen. Results indicated sensitivity of the ultrasonic wave velocities, waveforms, and amplitudes (cross-polarized S-waves) to the fracture orientation.