The aim of this study was to summarise the clinical evidence supporting almost 40 years of topical cadexomer iodine (CIOD) use in wound bed preparation by removing barriers to healing such as exudate, slough, bioburden, and infection and allowing chronic wound progression. A systematic review was conducted (Embase/PubMed, November 2020) to identify relevant comparative studies meeting inclusion criteria. Meta‐analyses were performed using a fixed‐effects (I2 < 50%) or random‐effects model (I2 ≥ 50%) depending on statistical heterogeneity. Dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD), with 95% confidence intervals. In total, 436 publications were identified of which 13 were comparative trials including outcomes of interest. Significant reductions in exudate, pus/debris, slough, bioburden, and infection were reported in chronic wounds treated with CIOD, compared with standard of care (SOC). Meta‐analyses highlighted the positive impact of CIOD on mean wound area reduction (MD = 2.35 cm2, 95% CI = 0.34–4.36, P = .0219) after eight weeks treatment and overall wound healing events compared to SOC; wounds including venous leg ulcers, diabetic foot ulcers, and pressure ulcers treated with CIOD were more than twice as likely to heal than those receiving SOC (RR = 2.30, 95% CI = 1.54–3.45, P < .0001). This meta‐analysis demonstrates the efficacy of CIOD on chronic wounds through removal of barriers to healing. CIOD should be considered in wound bed preparation and treatment protocols.