Substance P (SP), acting on the neurokinin‐1 receptor (NK‐1R), is a neuropeptide, involved in the inflammatory processes. It promotes vasodilatation and increases vasopermeability, thus ensuing extravasation and accumulation of leucocytes at sites of injury. The aim of this study was to assess the impact of SP signalling on the responses during staphylococcal infection and the accompanying arthritis. Three experiments were performed where NK‐1R−/− mice and controls were intravenously infected with different doses of Staphylococcus aureus. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. In addition, the impact of NK‐1R mutation on bacterial load in the kidneys as well as the phagocytic capacity of blood leucocytes were studied. Mice lacking the NK‐1R displayed significantly higher bacterial load in the kidneys and significantly more severe synovitis and cartilage/bone destruction than the controls when inoculated with 1.4 × 10⁷ staphylococci. Infection with 3.5 × 10⁸ CFU/mouse induced sepsis. Thus, 11 days after bacterial inoculation 15 of 19 mice in the NK‐1R−/− group had died versus 8 of 15 in the control group. Phagocytosis test revealed that significantly fewer macrophages from NK‐1R−/− mice were able to phagocytose S. aureus when compared with macrophages from congenic control mice. Blocking the biological responses to substance P via its receptor NK‐1R results in a less efficient clearance of bacteria leading to more severe arthritic lesions in mice.