This study investigates the influence of the wall opening ratio on the structural behavior of reinforced concrete (RC) frames with infill walls (IWs), focusing on the responses of columns, beams, and the first natural period T1. A finite element model incorporating stiffness degradation and gap elements was developed and validated against experimental results. Numerical analyses were conducted for four wall thicknesses (70, 110, 220, and 330 mm) and opening ratios ranging from 0 to 100%. Results indicate that in columns, lateral displacement ( \(\Delta\) ) increases significantly with the opening ratio, while bending moment (M) also increases and shear force (Q) decreases—demonstrating internal force redistribution from the IWs to the RC frame. In beams, deflection (f) increases markedly, especially beyond 60% opening ratio, while both M and Q decrease sharply, reflecting reduced wall–beam interaction. Thicker walls lead to smaller deformations and more uniform structural responses. The study also shows that T1 increases as the opening ratio rises and decreases as wall thickness increases, indicating a reduction in lateral stiffness caused by the infill walls. Based on the results, a 40% opening ratio is recommended as a practical limit to maintain overall structural stability, while reinforcement measures are advised for ratios exceeding 60%. The findings provide a quantitative basis for optimizing the seismic design of RC frames with IWs under lateral loading conditions.