Purpose: To evaluate the evidence on sperm DNA fragmentation (SDF) and its clinical applications in reproductive medicine, highlighting benefits, limitations, and guidelines for its use to assist clinicians in objective decision-making. Materials and Methods: A multidisciplinary team of clinicians and reproductive experts from the Global Andrology Forum (GAF) reviewed the latest evidence on SDF, covering indications, testing methods, recurrent pregnancy loss, varicocele and its repair, assisted reproductive technologies (ART), treatment of associated conditions, antioxidant therapy, and sperm selection for ART. Expert statements and recommendations were developed and graded with the GRADE system using a modified Delphi process. Results: Based on the GAF surveys, systematic reviews, and meta-analyses related to SDF, 52 experts introduced and scored 24 statements and recommendations using the GRADE system. Of these, 87.5% (21/24) achieved strong ratings, reflecting broad consensus, while 12.5% (3/24) were rated weak. The guidelines provide evidence-based recommendations for clinical scenarios, including the role of SDF in infertility, recurrent pregnancy loss, and ART outcomes. Conclusions: While there is growing interest and evidence regarding the clinical benefit of SDF testing and its utility in managing male infertility, significant gaps in the literature limit its routine use in clinical practice. The guidelines offer a structured framework for integrating SDF testing into male infertility management, emphasizing a tailored approach based on individual clinical scenarios. Clinicians must balance the benefits and limitations of SDF testing and antioxidant treatment to optimize care in reproductive medicine. These guidelines are critical for advancing evidence-based practices in male infertility management.