<p>Orthopedic infections, including osteomyelitis and prosthetic joint infection (PJI), are complicated clinical problems that urgently need to be paid attention to and solved. Clinically, antibacterial drug-loaded bone cement (ALBC) has been frequently used to treat localized orthopedic infections because of its strong local antimicrobial activity. While, ALBC faces the problem of poor therapeutic effect in clinical applications due to the development of bacterial resistance to antimicrobial drugs, as well as the limitations in the bone cement’s mechanical properties and drug release properties. Numerous research efforts are currently underway to create new composite bone cement by combining the use of a wide range of antimicrobial drugs, optimizing the preparation process of bone cement, introducing new antimicrobial agents and innovative materials to overcome the shortcomings of the conventional ALBC, expanding its potential for clinical use. However, the majority of related studies are performed on the in vitro level, and additional in vivo experimental data are required to confirm their efficacy and safety. This review summarizes the development of ALBC, with a focus on the research progress and innovative breakthroughs in drug selections, drug release mechanisms, and clinical applications, which is expected to provide a reference for the in-depth investigation of multifunctional bone cement and multidisciplinary cross-collaboration, as well as to expand the potential of bone cement for clinical applications.</p>