Field experience shows that horizontal well multi-stage fracturing technology can transform the volumetric pressure crack network in the formation and has been widely used in unconventional oil and gas resource exploitation. According to the requirements of horizontal well fracturing operations, this paper simulates the law of horizontal well fracturing in low-porosity and low-permeability sand-shale formation by large-mold fracturing tests and analyzes crack initiation and extension. The two completion methods of open-hole completion and casing perforation completion are considered, and the maximum and minimum horizontal principal stress difference is 10 and 4 MPa. The horizontal wellbore azimuth angle changes from 0 degrees to 90 degrees. The test results show that the principal stress difference has a great influence on fracture initiation. The smaller the stress difference, the higher the fracture initiation pressure and the more complicated the fracture initiation and extension. The fracture propagates along the axial direction of the wellbore, and then at both ends of the wellbore the fracture turns to the direction perpendicular to the direction of the minimum horizontal principal stress. The horizontal wellbore can form a transverse fracture by drilling along the direction of the minimum horizontal principal stress. This study is of great significance for understanding the fracture initiation and propagation law of horizontal well fracturing and can provide guidance for multi-stage fracturing operations of horizontal wells in unconventional reservoirs.