Abstract <p><i>Staphylococcus aureus</i> is a major cause of hospital-acquired pneumonia, with methicillin-resistant strains contributing significantly to prolonged illness and mortality. Methicillin-resistant strains can be responsible for up to 75% of infections in certain countries. Therefore, the problem is described as severe, and the search for alternative methods of treatment of such infections is currently one of the priorities in healthcare. Bacteriophages, although historically underutilized, are re-gaining interest for their potential in treating bacterial infections. However, they do have their limitations such as specific ranges of activity and resistance development. Combining phages with antimicrobial agents such as lactoferrin—a natural protein with antimicrobial and anti-biofilm properties—may improve treatment outcomes. In this study, we evaluated the efficacy of three Kayviruses paired with lactoferrin against MRSA in infected pulmonary epithelial cell cultures. The combination significantly reduced bacterial viability, protected human cells from cytotoxic effects of bacterial infection, and decreased inflammasome activation. These findings suggest that phage-lactoferrin combinations may offer a promising, safer alternative for managing MRSA-related pneumonia and reducing dependence on traditional antibiotics.</p> Key points <p>•<i>Phage lactoferrin mixture had no influence on A549 cells</i></p> <p>•<i>Lactoferrin increased phage efficacy and reduced influence of bacteria on cells</i></p> <p>•<i>Phage + Lf mixture limited inflammatory response similarly to phages and Lf alone</i></p>