In many parts of the world, antiseptic agents remain non-indicated in chronic wound care. In the current context of bacterial resistance to antibiotics and the development of new-generation antiseptic agents, wound antisepsis represents an asset for the prevention of wound infection. We aimed to evaluate four common antiseptic agents in chronic wound care complete healing. The review protocol was based on the Cochrane Handbook for Systematic Reviews of Intervention and devised in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement guidelines. Five databases and three clinical trials registries were searched from inception to 30 June 2021 without language restrictions. We included randomised trials evaluating the efficacy of antiseptic agents in chronic wound care in adults. Interventions considered were those using antiseptics for cleansing or within a dressing. Risk of bias was assessed using the bias excel tool provided by the Bristol Academy. Evidence quality was assessed using Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria. Of 838 studies, 6 were finally included, with a total of 725 patients. The included studies assessed iodine (cadexomer or povidone iodine) (n = 3), polyhexanide (n = 2), and octenidine (n = 1). Limited evidence suggested a better wound healing completion with iodine compared to saline (two randomised controlled trials (RCT), 195 patients, pooled RR 1.85 (95%CI (1.27 to 2.69)), moderate-quality evidence). There was not enough evidence to suggest a difference in wound healing using octenidine or polyhexamide. None of the antiseptic agents influenced adverse event occurrence compared to saline.