Two series of load-bearing horizontal-hole interlocking hollow concrete blocks, referred to as H-shaped series and cross-shaped series, were developed, including three geometric types: type BH-290 (H-shaped), type BH-240 (H-shaped), and type BC-240 (cross-shaped). The research presented in this article investigated the compressive behavior of the proposed load-bearing horizontal-hole interlocking hollow concrete blocks and aimed at analyzing the influence of geometric parameters on the block capacity. First, compressive tests of the horizontal-hole interlocking hollow concrete blocks were carried out. The compressive strength, elastic modulus, and compressive failure mechanism were analyzed. Second, the feasibility of the finite element analysis model was verified by experimental results presented in this article, as well as by available test data from other researchers. The influences of vertical ribs, horizontal ribs, and concrete strength on the compressive strength of horizontal-hole interlocking hollow concrete blocks were investigated. Ultimately, based on the numerical modeling results, linear equations were proposed to predict the compressive strength of H-shaped series and cross-shaped series blocks. The results show that the compressive strengths of types BH-240, BH-290, and BC-240 are 15.9, 13.4, and 13.0 MPa, respectively. For the H-shaped series, the core horizontal rib is the key part that can significantly constrain the vertical ribs so that the block can achieve higher compressive bearing capacity. For the cross-shaped series, core horizontal ribs cannot improve the compressive strength of the block because core horizontal ribs and joints near them become damaged early. Improving the concrete strength and the width of the vertical rib can effectively improve the compressive bearing capacity for both H-shaped and cross-shaped series blocks. The accuracy of the proposed equations for predicting the compressive strength of H-shaped and cross-shaped blocks is acceptable, according to the current verification.