Background Trigeminal neuralgia (TN) is characterized by brief, unilateral, sharp, stabbing, and shooting pain of the fifth cranial nerve. The objective of this systematic review with meta-analysis was to determine the effect of medications compared to placebo in adult patients with TN. Methods Review authors identified randomized placebo-controlled trials (RCTs) from PubMed, Web of Science, Cochrane, and EMBASE up to February 2021. We assessed the inclusion and exclusion criteria as well as the risk of bias of the studies based on the Cochrane Handbook. A total of 324 unduplicated references were scanned independently and reduced to eight relevant RCTs, with 89 patients included. Medications investigated included oral carbamazepine, subcutaneous sumatriptan, lidocaine (intranasal, 8% spray on the oral mucosa or intravenous), buprenorphine (ganglionic local opioid analgesia), and oral Nav1.7, a selective sodium channel blocker. Results Meta-analyses showed that overall patients receiving lidocaine reported a significantly lower post-treatment intensity of pain −3.8 points on a 0–10 scale (95% Cl = −4.653 to −2.873; P < 0.001). Patients who received lidocaine were 8.62 times more likely to have pain improvement than patients on placebo (P < 0.001). In one RCT, patients receiving oral carbamazepine showed a significant improvement in pain intensity of −32% compared to the placebo (P < 0.001). In one trial, patients receiving 3 mg subcutaneous sumatriptan had a significantly lower intensity of pain on average −6.1 points on a scale of 0–10 compared to placebo (P < 0.001) and a significant improvement in pain intensity of −75% compared to the improvement in the placebo group (P < 0.001). Patients who received subcutaneous sumatriptan were 10 times more likely to have pain improvement than those who received placebo (P = 0.001) in one study. Due to the unclear/high risk of bias and small sample size, the quality of the evidence for lidocaine in the treatment of TN was low. Conclusion Further studies are needed for carbamazepine, sumatriptan, buprenorphine, and oral Nav1.7 sodium channel blockers, as only one study reported outcomes.