Backround and objectives: White spot lesions (WSLs) represent a common enamel demineralization complication associated with fixed orthodontic treatment. Resin infiltration is widely used as a minimally invasive approach to arrest lesion progression and improve esthetics; however, the influence of lesion severity on treatment effectiveness remains insufficiently understood. This in vitro study aimed to evaluate the impact of WSL severity on resin infiltration performance under conditions simulating orthodontic demineralization. Material and Methods: Ninety extracted human premolars were subjected to controlled acidic exposure to produce mild, moderate, and severe lesions. All specimens were treated using a standardized resin infiltration protocol. Lesion depth, resin penetration, optical masking effect (ΔE), and surface microhardness were evaluated using confocal microscopy, spectrophotometry, and Vickers hardness testing. Results: Lesion depth increased significantly with demineralization duration (p < 0.001). Resin penetration showed a strong positive correlation with lesion depth (r = 0.81), while infiltration efficiency was highest in moderate lesions. Optical masking effectiveness decreased significantly with increasing lesion severity (p < 0.01). Surface microhardness improved significantly after infiltration in all groups, with the greatest recovery observed in moderate lesions. Conclusions: Lesion severity significantly influences the clinical performance of resin infiltration. Early and moderately developed WSLs respond more favorably to infiltration treatment, emphasizing the importance of timely intervention during orthodontic therapy.