Administration of oropharyngeal colostrum (OPC) is safe, feasible, and potentially beneficial in preterm infants. We aimed to assess the effects of OPC in preterm infants. A systematic review of randomized controlled trials (RCTs) and non-RCTs of OPC administration in preterm infants was conducted. We searched MEDLINE via PubMed and Ovid, EMBASE, the Cochrane Central Register of Controlled Trials, Emcare databases, abstracts of Pediatric Academic Societies meetings, and gray literature in April 2018. Six RCTs (n = 269) and 4 non-RCTs (n = 737) were included. One RCT (n = 40) focused on enteral bovine colostrum and hence was excluded from our review. Five of the 6 RCTs had unclear risk of bias in many domains of assessment. Meta-analysis (random effects model) of RCT data showed no significant difference in ≥stage 2 necrotizing enterocolitis (RR: 0.83; 95% CI: 0.39, 1.75; P = 0.62), late-onset sepsis (RR: 0.78; 95% CI: 0.50, 1.22; P = 0.28), all-cause mortality (RR: 0.74; 95% CI: 0.27, 2.06; P = 0.56); duration of hospital stay (mean difference [MD]: -1.65 d; 95% CI: -10.09, 6.80; P = 0.70), and time to full feeds (MD: -2.86 d; 95% CI: -6.49, 0.77; P = 0.12). Meta-analysis of data from non-RCTs also showed no benefit for any of these outcomes. OPC increased secretory IgA and lactoferrin concentrations (4 RCTs), and had only a transient effect on the oral microbiome (1 RCT). There were no adverse effects (e.g., aspiration) of OPC. The overall quality of evidence (Grades of Recommendation, Assessment, Development, and Evaluation analysis) was very low. Adequately powered RCTs are needed to confirm the nutritional and immunomodulatory benefits of OPC in preterm infants.