Aim: This systematic and meta-analysis was conducted to evaluate the efficacy and safety of insulin, metformin, and glyburide on perinatal complications for gestational diabetes mellitus (GDM). Methods: Medline (PubMed), EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials [CENTRAL], and Cochrane Methodology Register), Web of Science (Science and Social Science Citation Index), and ClinicalTrials (Clinicaltrials.gov) were searched, as well as manual searching. We included randomized controlled trials comparing efficacy and safety of metformin versus glyburide, metformin versus insulin, and glyburide versus insulin in patients with GDM. Results: We included 32 articles including 5,964 patients published from inception to July 2020. Compared with insulin, metformin was more effective at lower incidence of macrosomia (RR: 0.66, 95% CI: 0.50–0.88, p = 0.005), lower incidence of neonatal intensive care unit admission (RR: 0.78, 95% CI: 0.67–0.91, p = 0.002), less neonatal hypoglycemia (RR: 0.67, 95% CI: 0.56–0.80, p < 0.0001), decreased birth weight (BW) (SMD: −0.37, 95% CI: −0.62 to −0.12, p = 0.004), lower incidence of large for gestational age (RR: 0.76, 95% CI: 0.50–0.90, p = 0.002), shorter gestation age at delivery (MD: −0.22, 95% CI: −0.34 to −0.10, p = 0.0002), lower maternal weight gain (MD: −1.41, 95% CI: −2.28 to −0.55, p = 0.001), less incidence of caesarean section delivery (RR: 0.86, 95% CI: 0.78–0.95, p = 0.0004), lower maternal postprandial blood glucose (SMD: −0.41, 95% CI: −0.72 to −0.11, p = 0.008), and lower incidence of pregnancy-induced hypertension (RR: 0.47, 95% CI: 0.27–0.83, p = 0.01). However, glyburide, compared with insulin, was associated with higher BW (MD: 54.95, 95% CI: 3.87–106.03, p = 0.03) and increased the incidence of neonatal hypoglycemia (RR: 1.52, 95% CI: 1.12–2.07, p = 0.007). Meanwhile, compared to glyburide, metformin was associated with higher maternal fasting blood glucose (SMD: 0.20, 95% CI: 0.05–0.36, p = 0.01) and lower incidence of induction of labor (RR: 0.76, 95% CI: 0.59–0.97, p = 0.03). Conclusions: This review suggests that metformin can decrease the incidence of perinatal complications, and it should be considered as a generally safe alternative to insulin.