Background/Objectives: Demineralization around orthodontic brackets may compromise enamel integrity and alter the mechanical stability of the bracket-adhesive-enamel interface, thereby influencing bond performance and clinical outcomes. This study aimed to evaluate the effect of enamel demineralization on the fatigue-based shear bond strength (SBS) of different orthodontic brackets. Methods: Seventy-five extracted maxillary premolars subjected to demineralization were allocated into five groups (n = 15 per group). Victory metal (Group 1), APC Clarity Advanced ceramic (Group 2), Clarity Self-ligating ceramic (Group 3), Gemini metal (Group 4), and Clarity Advanced ceramic (Group 5) brackets were bonded to the tooth surfaces using Transbond XT (3M Unitek, Monrovia, CA, USA). The mean demineralization values of the specimens were recorded before demineralization (T0) and after exposure to an artificial cariogenic environment (T1). Fatigue-based SBS was evaluated under cyclic loading (10 N, 0.5 Hz) at a crosshead speed of 300 mm/min using a closed-loop controlled, low-cycle fatigue testing machine and expressed as the number of shear strokes to failure. The level of statistical significance was set at p < 0.05. Results: No significant differences in demineralization were observed among the groups at T0 (p > 0.05); however, all groups showed significant increases at T1 (p < 0.05), with Group 1 demonstrating significantly lower demineralization than the other groups (p < 0.05). Fatigue-based SBS was higher in Groups 1, 3, and 5 than in Groups 2 and 4, as indicated by a greater number of shear strokes to failure (p < 0.05). In Groups 2 and 4, a statistically significant negative correlation was observed between changes in enamel demineralization and the number of shear strokes to failure (p < 0.05). No hard tissue damage was observed in Group 5 during fatigue testing. Conclusions: Increased demineralization may adversely affect fatigue-based SBS and increase the risk of hard tissue damage. Under plaque-related demineralization conditions, Victory metal and Clarity Advanced ceramic brackets may demonstrate more favorable fatigue bond behavior; however, further in vitro and in vivo studies are required to confirm these findings.