Background: Spironolactone is the main addition for triple therapy for resistant hypertension, which has been proven by previous studies about how effective the drug is on reducing blood pressure. Renal denervation (RDN) is a catheter-based ablation procedure designed to treat resistant hypertension (RH). Both of these interventions are considered the main choices on treating resistant hypertension, however the use of spironolactone and renal denervation to decrease blood pressure in individuals with resistant hypertension has not before been compared in a systematic study. Methods: We performed the present systematic review according to preferred items in the 2020 PRISMA. A systematic search was conducted through Pubmed, Sciencedirect, Scopus, and Web of Science selecting randomized control study until July 2022 Results and Discussion: Our search yielded 987 studies of which we included 6 studies for the final analysis. A total of 224 patients were treated with spironolactone and 211 patients treated with RDN, however 1 study performed RDN combined with PVI. From the 6 studies included in this review, it has been found that spironolactone has a better lowering effect on both 24-hour and office blood pressure. Conclusion: Spironolactone is more effective than renal denervation in reducing blood pressure in patients with resistant hypertension.