Abstract: Karst-included damage is a key intrinsic factor controlling the instability of limestone slopes. This study aims to systematically investigate the mechanical response characteristics and failure mechanisms of porous limestone. A multi-scale research framework integrating physical experiments and numerical simulations was adopted. Uniaxial compression tests and PFC3D discrete element modeling were conducted to quantitatively analyzes the coupled effects of the number of circular holes (1-4) and their spatial arrangement (horizontal/vertical) on the mechanical properties, degradation patterns, and failure modes of limestone. The research findings indicate that: (1) A nonlinear attenuation model between the number of circular holes and peak strength was established, revealing the strength degradation patterns under different arrangement modes. Specimens with horizontal arrangement exhibited exponential decay characteristics in peak strength, elastic modulus, and peak strain, whereas vertically aligned specimens showed a linear decreasing trend. Notably, the degradation effect on strength parameters was 37.2% more significant in horizontal arrangements compared to vertical arrangements. (2) Based on Digital Image Correlation (DIC) technology and PFC3D simulations, the evolution of crack propagation was systematically revealed. The study found that single-hole specimens exhibited typical diagonal shear failure, whereas multi-hole specimens (n ≥ 2) evolved into vertically through-going splitting failure. This finding verifies the directional control effect of the spatial configuration of circular holes on the failure mode. (3) Discrete element back-analysis quantitatively characterized the cavity effect on crack initiation stress. As the number of circular holes increased from 1 to 4, the crack initiation stress decreased significantly from 166.86 MPa to 154.32 MPa, representing a reduction of 12.5%. The findings provide a theoretical basis and technical support for stability evaluation of rock masses geological hazard prevention and control in karst regions.