Abstract Introduction Peyronie’s Disease (PD) is a fibrotic disorder of the tunica albuginea leading to penile curvature, pain, and sexual dysfunction. Intralesional therapies are a non-surgical treatment strategy aiming to modulate fibrosis and reduce deformity. Intralesional verapamil, a calcium channel blocker, has been used to inhibit fibroblast proliferation and collagen synthesis, but its clinical effectiveness remains controversial. Despite widespread use, existing literature is heterogeneous in design and outcome measures. Objective We aimed to systematically review and summarize the evidence from prospective clinical trials assessing the efficacy and safety of intralesional verapamil. Methods Data extraction was carried out independently by the presenting author and a board-certified librarian. We conducted a structured literature search using PubMed, Scopus, and Web of Science for prospective trials from 2015-2025 evaluating intralesional verapamil use in patients with PD. Inclusion criteria were: [1] prospective study design, [2] adult patients with a clinical diagnosis of PD, [3] use of intralesional verapamil as monotherapy or in combination, and [4] reported outcomes on penile curvature, and sexual function. Data extraction included study design, sample size, outcome measures, and follow-up. Risk of bias and quality assessment was performed using the Cochrane Risk of Bias 2.0 scale. Results A total of 199 studies were screened. A total of 6 prospective trials were selected after excluding trials who were not compliant with our criteria, reporting on 754 patients with 1 to 24 months follow-up. RCTs evaluated were of moderate quality with a low risk of bias, but 3/6 had a high risk of bias. Across randomized trials, verapamil monotherapy resulted in modest improvements in curvature (range mean change in penile curvature -2° to -16°). In contrast, combination therapies or alternative injectables such as collagenase (CCH) and tiocolchicine showed greater curvature improvements (–28° in Chung; ~10° in Toscano). In non-randomized studies comparative studies, verapamil (Ver) demonstrated consistent improvement in penile curvature (~4.5° reduction [Cocci 22]), with sustained results at 24 months. Nevertheless, in these studies HA was superior to Verapamil (~9.5° reduction). Erectile function, measured by IIEF-5, improved modestly across studies, with the greatest gains observed in combination therapy arms or HA groups. Conclusions Intralesional verapamil offers modest improvements in penile curvature and erectile function in Peyronie’s Disease but appears less effective than alternative agents such as hyaluronic acid, collagenase, or combination therapies. Heterogeneity in trial design and moderate risk of bias limit definitive conclusions. Further high-quality, blinded randomized trials are needed to establish optimal intralesional treatment strategies. Disclosure No