This case report presents a rare and compelling instance of cephalosporin-induced autoimmune hemolytic anemia (AIHA) in a surgical patient who received common perioperative prophylactic antibiotics of cephalosporin. 2 weeks following the elective removal of an ulcerated skin lesion, the patient exhibited a precipitous decline in hemoglobin levels manifesting as a presentation to the Emergency Department with acute shortness of breath. A full blood count revealed and haemoglobin of 39g/L and the patient had an admission under haematology where extensive investigation revealed a robust immune response against red blood cells, consistent with autoimmune hemolytic anemia. The temporal association with cephalosporin administration during the perioperative period prompted a closer examination of drug-induced hemolytic reactions. The patient's clinical course was marked by severe anemia necessitating multiple blood transfusions over two separate admissions, and an extended course of corticosteroid therapy to suppress the autoimmune response. This presentation details the diagnostic challenges encountered, including the distinction between drug-induced and idiopathic AIHA, and a rare complication of commonly prescribed antibiotics (cephazolin and cephalexin) to underscores the importance of diligent prescription of perioperative antibiotic prophylaxis. This case report contributes to the growing body of evidence highlighting the potential for cephalosporin-induced immune-mediated adverse effects and emphasizes the need for individualized patient risk assessment and tailored prophylactic strategies in surgical settings. The insights gained from this case will contribute to quality and safety in surgical practice.