Before the introduction of routine antibiotic administration, the rate of postcesarean infection exceeded 30% to 50%. Since the 1970s, postpartum infection occurs in approximately 1% to 2% of patients after vaginal birth and in 5% to 20% following cesarean delivery. Evidence from randomized clinical trials and systematic reviews has demonstrated that the administration of a single dose of antibiotics within 60 minutes before skin incision significantly reduces maternal infection-related morbidity without adverse neonatal outcomes. These results have informed clinical guidelines of professional organizations. Antibiotic selection is empiric and primarily guided by knowledge of the microbiology of intra-amniotic and puerperal infection. Cefazolin is the standard prophylactic agent due to its broad-spectrum activity, favorable pharmacokinetics, and established safety. However, its lack of activity against organisms such as Ureaplasma species has motivated investigation of adjunctive azithromycin, particularly in high-risk or unscheduled cesarean deliveries, where randomized trials and meta-analyses show additional benefit in reducing wound infections and endometritis. For patients with severe beta-lactam allergies, clindamycin and gentamicin are commonly used, although use of these agents is associated with higher rates of surgical site infection, increased antimicrobial resistance, and risks such as nephrotoxicity and necrotizing enterocolitis due to Clostridioides difficile infection. Special considerations include obesity, which doubles the risk of surgical site infection and alters antibiotic pharmacokinetics, prompting recommendations for a 3-gram cefazolin dose in patients ≥120 kg. Prolonged operative time and excessive blood loss also warrant intraoperative redosing to maintain therapeutic levels. In addition, emerging evidence suggests that adjunctive postcesarean antibiotic administration (eg, cephalexin with metronidazole) may reduce wound complications in obese women, although professional guidelines remain in evolution. In summary, judicious use of antibiotic prophylaxis is essential to reduce cesarean-related infections and optimize maternal outcomes, while continued research seeks to refine strategies that mitigate unintended neonatal consequences.