Although CAD/CAM (computer-aided design/computer-aided manufacturing) restorations act as a favorable alternative to conventional metal-ceramic restorations for fixed dental prostheses, little is known about their intermediate and persistent clinical performance. This systematic review and meta-analysis aimed to assess the clinical performance in terms of biological, technical, and esthetic aspects and the survival and success ratios for single full crowns (SFCs) and fixed partial dentures (FPDs) fabricated by CAD/CAM and conventional techniques and according to the materials used (zirconia {ZC} and lithium disilicate {LD}). The population, intervention, control, outcome, and study design (PICOS) strategy was used to electronically search key terms in the PubMed, Cochrane Library, Embase, and Wiley Online databases for randomized control trials (RCTs) and cohort studies. The bias risks for RCTs and cohort studies were assessed using the Cochrane collaboration tool and the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using Rev5 from Cochrane. A total of 13 studies reporting on 1598 restorations in 1161 patients with a mean observation period of 3.6 years (minimum-maximum: 1-9.3 years) met the inclusion criteria. Meta-analysis of the included studies indicated that CAD/CAM manufacturing resulted in 1.17, 1.14, and 16.88 (95% CI: 0.64-2.17, 0.86-1.52, 7.59-37.56) higher biological, technical, and esthetic complications than conventional manufacturing of restorations. However, the difference was significant for esthetic complications only (p<0.00001). A significant difference was observed for all biological, technical, and aesthetic aspects between SFCs and FPDs (odds ratio {OR} = 2.61 vs. 1.78, 95% CI: 1.92-3.56 vs. 1.33-2.38; p<0.00001). The survival ratio of SFCs was 2.69 (95% CI: 1.98-3.65), significantly higher compared to the 1.76 (95% CI: 1.31-2.36) of FPDs (p<0.00001). The success ratio of FPDs at 1.18 (95% CI: 0.83-1.69) was significantly lower compared to SFCs at 2.36 (95% CI: 1.68-3.33). The clinical performance of LD with 2.42 (CI: 1.16-5.03) was significantly higher compared to ZC with 2.22 (CI: 1.78-2.77) (p<0.00001). The biological, technical, and aesthetic behaviors showed similar clinical outcomes between the CAD/CAM and conventional groups. LD could be a good alternative to zirconia, but its intermediate or persistent clinical performance needs to be evaluated. Overall, zirconia and CAD/CAM techniques must evolve further to outclass the conventional techniques used in the fabrication of SFCs and FPDs.