Staphylococcus aureus (S. aureus), an important pathogen of both humans and animals, can cause a variety of infections at any site of the body. The evolution of S. aureus resistance is no-torious, and the widespread of drug-resistant S. aureus, especially methicillin-resistant S. aureus (MRSA), has made the treatment difficult in recent decades. Nowadays, S. aureus is among the leading causes of bacterial infections, creating an urgent need for the development of novel antibac-terial agents. Ciprofloxacin, characterized by high clinical efficacy, is a broad-spectrum antibacteri-al agent with frequency of prescription for various Gram-positive and Gram-negative pathogens, many of which are resistant to a wide range of antibiotics. However, the long-term and widespread use of this antibiotic has led to the emergence of ciprofloxacin-resistant pathogens, and ciprofloxa-cin-resistant S. aureus has been noted in clinical practice. Ciprofloxacin hybrids have been recog-nized as advanced chemical entities to simultaneously modulate multiple drug targets in bacteria, so ciprofloxacin hybrids have the potential to overcome drug resistance. The present review provides an overview of ciprofloxacin hybrids with anti-S. aureus potential that has been reported in the last decade with an emphasis on their structure-activity relationships and mechanisms of action.