The aim of this study was to evaluate the topography and the fatigue performance of lithium disilicate glass-ceramic after surface grinding through different laboratory protocols used to simulate the Computer-aided design/Computer-aided manufacturing (CAD/CAM) milling. Ceramic discs (IPS e.max CAD, Ø = 13.5 mm × 1.2 mm of thickness) were produced through different methodologies: milling in CAD/CAM system (CAD/CAM group); produced in-lab with a polished surface (POL group); or produced through in-lab methods and randomly distributed into five groups according to different grinding protocols to simulate the CAD/CAM milling [grinding with a CAD/CAM bur coupled to a mandrel (CAD/CAM Bur group); fine diamond bur using oscillatory movements (DBO group); fine diamond bur in x and y axes of the disc (DBXY group); #60-grit silicon carbide sandpaper (SiC group); and #60-grit wood sandpaper (WS group)]. The specimens were fatigue tested (n = 15) according to the step-stress method (initial load: 60 N; step-size: 20 N; 10,000 cycles/step; 20 Hz frequency). A roughness analysis was performed on all specimens, while fractal dimension (FD) and fractography were performed on representative samples. The Kaplan-Meier analysis showed that the POL (293.3 N) group presented better fatigue performance (higher load and number of cycles for failure) (p < 0.05) than the other groups (CAD/CAM = 222.7 N; CAD/CAM Bur = 181.3 N; DBO = 184.0 N; DBXY = 192.0 N; SiC = 182.6 N; WS = 182.6 N). For roughness, only the SiC (Ra = 1.616; Rz = 10.465) and WS (Ra = 1.673; Rz = 10.655) groups produced statistically similar Ra (μm) and Rz (μm) values to the CAD/CAM (Ra = 1.628; Rz = 9.571) group (p > 0.05). The surface created by CAD/CAM milling and POL group exhibited more complexity (FD) higher values than the experimental groups. For the ceramic surface topography images, the CAD/CAM milling visibly produced a uniform surface compared to the other groups; however, the POL group was the smoothest. The DBO, DBXY, SiC, and WS groups resulted in similar characteristics of surface topography. Therefore, although the SiC and WS groups showed similar roughness to the control group (CAD/CAM), no in-lab simulation method was fully capable to mimic the mechanical performance of the CAD/CAM-milled lithium disilicate glass-ceramic.