The relationship between wound irrigation and healing has been recognized for centuries. However, there is little evidence and no official recommendations from any health care organization regarding best wound irrigation practices. This is the first review of wound irrigation that systematically summarizes the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and distills the evidence into a practical format. In this comprehensive review, the authors outline the irrigation fluids and delivery methods used in the identified studies, analyze reported treatment outcomes, summarize irrigation effectiveness, and propose evidence-based guidelines to improve wound healing outcomes and enhance the consistency of wound irrigation. Thirty-one high-quality studies with a combined total of 61,808 patients were included. Based on the current evidence provided by this review, the authors propose the following guidelines: (1) acute soft-tissue wounds should receive continuous gravity flow irrigation with polyhexanide; (2) complex wounds should receive continuous negative-pressure wound therapy with instillation with polyhexanide; (3) infected wounds should receive continuous negative-pressure wound therapy with instillation with silver nitrate, polyhexanide, acetic acid, or povidone-iodine; (4) breast implant wounds should receive gravity lavage with povidone-iodine or antibiotics; and (5) surgical-site infection rates can be reduced with intraoperative povidone-iodine irrigation.