Background/Objectives: Fabrication of ceramic restorations with higher performance, biocompatibility, and mechanical durability, as well as excellent optical properties, is challenging. Therefore, this study was designed to investigate the mechanical properties and surface roughness of different glass ceramics manufactured with CAD/CAM and pressed techniques before and after exposure to simulated gastric acidic challenge. Methods: Lithium disilicate-based (LDS) ceramic, advanced lithium disilicate (ALDS), and zirconia-reinforced lithium silicate (ZLSC), were manufactured with two techniques. Disc-shaped (N = 336) specimens were used to test the biaxial flexural strength (BFS), while surface microhardness and surface roughness were evaluated before and after exposure to hydrochloric acid (34–37% concentration and 1.2 pH for 24 h). The results were statistically evaluated using two- and one-way ANOVA, Tukey’s post-hoc and Student’s t-test. Results: Both CAD and pressed types of LDS ceramic IPS e.max, showed significantly highest BFS and microhardness before and after acidic challenge (p = 0.01 and <0.01, respectively). ALDS and ZLSC showed significantly lower roughness before acidic aging, while all groups showed no significant difference after aging. Conclusion: Pressed groups showed better mechanical performance than CAD groups. LSD (IPS e.max types) continuously showed a better mechanical performance than modified LDS. ALDS and ZLSC showed the best performance in terms of surface smoothness, but after acidic exposure, no significant difference was observed compared to the other groups.