Background: Tyrosine kinases such as VEGFR, KIT, RET, MET are implicated in development and progression of several solid tumors. Cabozantinib is an oral multiple tyrosine kinase inhibitor and has shown survival benefits in several solid tumors. Yet, there are notable toxicities. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of palmar-plantar erythrodysesthesia (PPE) and hypertension in patients with metastatic solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention PPE and hypertension as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% CI. Random effects model was applied. Heterogeneity was assessed using I2 statistic. Results: 4 phase III RCTs with total of 2,703 patients, comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone, were included. I2 statistic was 70.70, suggesting some heterogeneity among RCTs. All grade-PPE incidence was 666 (39.3%) in cabozantinib arm vs 38 (3.76%) in control arm with a RR of 11.378 (95% CI: 6.545–19.782; P<.0001). The absolute RD was 0.383 (95% CI: 0.294–0.473; P<.0001). High-grade PPE was reported in 172 (10.15%) in cabozantinib group vs 3 (0.29%) in control group with a RR of 19.077 (95% CI: 5.733–63.476; P<.0001). The RD was 0.105 (95% CI: 0.049–0.160; P<.0001). The overall incidence of hypertension was noted at 524 (30.95%) in cabozantinib arm vs 84 (8.31%) in control arm. The pooled RR of hypertension was 4.131 (95% CI: 2.656–6.425; P<.0001) and RD was 0.240 (95% CI: 0.186–0.295; P<.0001). High-grade hypertension was reported in 276 (16.30%) in cabozantinib group vs 41 (4.05%) in control group with a RR of 4.324 (95% CI: 2.484–7.525; P<.0001) and RD was 0.115 (95% CI: 0.085–0.144; P<.0001). Conclusion: Our meta-analysis demonstrated that cabozantinib contributed to significant toxicity of any-grade and high-grade PPE as well as hypertension, with a RR of 19.07 for grade 3 and 4 PPE. Recognizing these toxicities and prompt intervention with proper supportive care may enhance patients’ quality of life, ultimately leading to better compliance.