The study aims to evaluate the effect of finishing and polishing protocol after CAD/CAM grinding and surface treatments of bonding surface on the topographical characteristics and fatigue behavior of 4YSZ adhesively luted to an epoxy resin substrate. Ninety 4YSZ discs (IPS e.max ZirCAD MT, Ivoclar AG) (Ø = 10 mm, thickness = 1 mm) were obtained, submitted to in-lab simulation with a CAD/CAM system bur, and randomly allocated into six groups (n = 15) based on 'Surface condition' (with or without finishing and polishing) and 'Surface treatments' (no treatment, air abrasion with 45 μm aluminum oxide and glaze spray application). The surface roughness of all samples was measured, and the discs were luted with resin cement onto an epoxy resin substrate to be tested under cyclic fatigue (step-stress approach: 20 Hz, 5,000 cycles for piston accommodation in the first step, followed by 10,000 cycles per step with a step size of 100 N, starting at 100 N until failure). The results indicated that surface roughness (Ra and Rz) decreased in the groups with polishing and finishing protocol, with no significant differences between surface treatments in groups without finishing and polishing. The air abrasion groups (whit and without finishing and polishing) showed superior fatigue performance, comparable to no treatment with polishing and finishing. While the groups no treatment without finishing and polishing, treated with glaze spray without finishing and polishing and treated with glaze spray with finishing and polishing exhibited inferior fatigue behavior. In conclusion, while the finishing and polishing protocol can minimize defects and influence the fatigue behavior of 4YSZ, its effect is not significant when combined with surface treatments. The surface treatment, particularly air abrasion, plays a more decisive role in improving fatigue performance, proving to be the most effective approach.