The objective of the study was to systematically summarize current evidence on the effectiveness of pre-surgical infant orthopedics (PSIO) in cleft lip and palate (CLP) patients. Electronic and manual searches were conducted, and using specific inclusion and exclusion criteria, data extraction and analysis was performed by two independent investigators. When possible, overall pooled estimates with 95% confidence intervals were obtained using the random-effects model. Twenty-four of 885 original studies met the inclusion criteria and were included in the qualitative synthesis, whereas 10 of them were included in the quantitative synthesis (meta-analysis). Except for the variable M-T-C(5) assessing maxillary arch form, which presented an increase at 48 months of follow-up, all other variables concerning craniofacial and dentoalveolar changes demonstrated no significant differences, indicating that PSIO treatment has no effect on CLP patients. The limited evidence derived from this study does not seem to support the short- or long-term effectiveness of PSIO in CLP patients.