The efficacy of renal sympathetic denervation (RSD) in the treatment of uncontrolled hypertension (HTN) remains uncertain. A systematic review of randomized controlled trials was performed to evaluate the efficacy and safety of RSD for resistant HTN. PubMed, EMBASE, MEDLINE, Cochrane, Directory of Open Access Journals, CINAHL, and Google Scholar were searched from January 01, 2001, through July 30, 2020. Randomized controlled trials comparing RSD with the sham procedure for uncontrolled HTN were selected. The primary efficacy outcome was the reduction in ambulatory systolic blood pressure. We used random-effects models. Nine prospective clinical trials met the inclusion criteria. The ReSet and Symplicity HTN-3 Trial showed no significant changes because of discrepancies in complete circumferential ablation during RSD. The Relief study, The Radiance HTN solo, and the SPYRAL HTN OFF medical trials showed a significant reduction in systolic blood pressure in the group that had undergone the intervention compared with the sham group attributed to rigorous trial design. In conclusion, our systematic review suggests that efficacy of RSD seems to be superior to sham-controlled interventions provided circumferential denervation is performed. However, difference in efficacy is marginal.