A total of 20 lithium disilicate glass-ceramics (IPS e.max CAD, Ivoclar Vivadent) and 20 resin nano-ceramic (Voco Grandio Blocks) onlay restorations were performed in 20 patients using a split-mouth design to compare the two-year clinical performance of lithium disilicate and resin nano-ceramic onlay restorations. Both restorations were evaluated at baseline, one-year, and two-year clinical follow-ups based on the modified United States Public Health Service (USPHS) criteria. Chi-square and Fisher's exact tests showed no statistically significant difference between Voco Grandio and IPS e.max ceramic restorations for all evaluated parameters during the different follow-up periods (p > 0.05). Cochrane's and MC-Nemar's tests indicated statistically significant differences regarding color match within the Voco Grandio group. They also indicated statistically significant differences in marginal discoloration, marginal adaptation, surface texture, and postoperative hypersensitivity within both ceramic material groups (p < 0.05). Kaplan-Meier curve indicated that the survival rate of both ceramic materials was 90%. After two years of clinical service, IPS e.max CAD and Voco Grandio onlay restorations exhibited similar clinical performance.