A horizontal well with hydraulic fractures is key to forming a fracture network in oil shale for the generated hydrocarbon flows. By considering the influence of anisotropic strength, a prediction model is proposed for fracture initiation by studying different fracture initiation modes (FIMs) in oil shale: failure of the intact rock matrix and of the bedding planes. Through a case study on Nong’an oil shale, the influences of wellbore trajectory and bedding planes on the fracture initiation pressure (FIP), location (FIL), and FIM were analyzed and the induced changes in wellbore trajectory design were concluded. The preferred angle between the wellbore axis and the minimum horizontal principal stress was the same of 90° or 270°, when the lowest required FIP corresponded to the failure of the intact rock matrix. However, when the angle corresponded to the failure of the bedding planes, the preferred direction of the wellbore axis was away from the fixed direction and not corresponding to the lowest required FIP due to the fracture morphology. The error between the theoretical and experimental results ranges from 7% to 9%. This research provides a framework for the design of horizontal wellbore trajectories in oil shale, for easier fracture initiation and more complex fracture networks.