The effectiveness of antibiotic prophylaxis (AP) in craniotomies has been clarified through the accumulation of evidence and increased antibiotic knowledge. This paper focuses on the use of AP in craniotomies during different historical periods and collects highly relevant evidence on this issue. This review surveys different AP guidelines and explains why cefazolin was selected by most guidelines. Recent prominent topics, including strategies to update and implement guidelines and antibiotic efficacy in postoperative meningitis and surveillance and decolonization therapies for methicillin-resistant Staphylococcus aureus, are discussed.