<p>Infection remains one of the most feared complications of penile prosthesis implantation (PPI), with implications for patient morbidity, psychological burden, and healthcare costs. Although infection rates have declined due to advances in device coatings, surgical techniques and perioperative care, emerging pathogens and antibiotic resistance continue to challenge clinical outcomes. This narrative review explores recent infection-preventing strategies, including antibiotic prophylaxis (APX), across the preoperative, intraoperative, and postoperative phases of PPI. Key themes include comorbidity optimization, urine culture management, and preoperative antiseptic protocols. Intraoperative innovations such as the no-touch technique, targeted irrigation regimens, and antimicrobial-coated implants have shown significant infection reduction. However, evidence for routine postoperative antibiotic use remains inconclusive, and conservative management of infections is limited to select cases. With changing microbial patterns—including increasing fungal and gram-negative organisms—tailored antibiotic approaches and emerging tools like next-generation sequencing may help refine treatment. A multidisciplinary, evidence-based strategy remains essential to further reduce infection rates and optimize patient outcomes in PPI.</p>