In this study, the strength and failure mechanism of red sandstones with combined defects were investigated by uniaxial compression tests on red sandstones with different crack angles using two-dimensional particle flow code numerical software, and their mechanical parameters and failure process were studied and analyzed. The results showed that the mechanical characteristics such as peak strength, peak strain, and elastic modulus of the samples with prefabricated combined defects were significantly inferior than those of the intact samples. With increasing crack angle from 15° to 60°, the weakening area of cracks increased, elastic modulus, peak strength, and peak strain gradually reduced, the total number of cracks increased, and more strain energy was released. In addition, the samples underwent initial brittle failure to plastic failure stage, and the failure form was more significant, leading to peeling phenomenon. However, with increasing crack angle from 75° to 90°, the crack-hole combination shared the stress concentration at the tip of the crack-crack combination, resulted in a gradual increase in elastic modulus, peak strain and peak strength, but a decrease in the number of total cracks, the release of strain energy reduced, the plastic failure state weakened, and the spalling phenomenon slowed down. On this basis, the samples with 30° and 45° crack-crack combination were selected for further experimental investigation. Through comparative analysis between the experimental and simulation results, the failure strength and final failure mode with cracks propagation of samples were found to be relatively similar.