Background and Objectives We conducted a systematic review and meta-analysis to investigate the role of vascular endothelial growth factor (VEGF) inhibitors and immune checkpoint inhibitors (ICIs) in preventing the development of brain metastases (BMs). Methods We searched MEDLINE, Embase, Cochrane Database, and Google Scholar between January 1, 2000, and June 1, 2020. Included studies were randomized controlled trials (RCTs) of adults with systemic cancer that reported the incidence of BMs treated with and without VEGF inhibitors, as well as observational studies of adults with systemic cancer that reported the incidence of BMs treated with and without ICIs (no RCTs addressed the ICI question). Pooled relative risks (RR) were computed with a binary random-effects model. Results A search for VEGF and incidence of new BMs revealed 7 studies (6,212 patients with breast, colon, and non–small-cell lung cancer). Meta-analysis showed a lower incidence of new BMs compared to control (RR 0.71, 95% confidence interval [CI] 0.56–0.89, p = 0.003). A search for ICIs and incidence of new BMs yielded 8 studies (732 patients with non–small-cell lung cancer or metastatic melanoma) in which ICIs were used as an adjunct to radiosurgery. Meta-analysis showed a lower incidence of out-of-treatment-field BMs with ICIs compared to controls at 1 year (RR 0.65, 95% CI 0.49–0.88, p = 0.005). The overall Grading of Recommendations, Assessment, Development and Evaluations score for the evidence evaluating the role of bevacizumab and ICIs was high and moderate, respectively. Discussion VEGF and ICIs may have a role in prophylaxis against BM in patients with solid tumors.