Neurologic injury and selective blockage of sensory nerve endings is associated with impaired fracture healing, however, the role of specific neurotransmitters has not been sufficiently investigated. Our aim was to investigate the impact of specific Substance P-receptor blockage on fracture healing, since the neuropeptide Substance P has both neurogenic and osteogenic activity. After intramedullary stabilization, an isolated femur fracture was induced in 72 Sprague-Dawley rats. In the NK1-R group, the neurokinin-1-tachykinin receptor for substance P was blocked by a specific antagonist (SR140333) for the first two weeks after fracture induction. The control group only received vehicle. Gene-expression, histology, micro-computed tomography, and biomechanical tests were performed. NK1-receptor blocking suppressed osteocalcin expression at one week, collagen 1A2 expression at one and two weeks and collagen 2A1 expression at 2 weeks after fracture induction. Biomechanical testing revealed a significant reduction in maximal load to failure in the NK1-R group at 6 weeks (69.78 vs. 155.45 N, p = 0.029) and at 3 months (72.50 vs.176.33 N, p = 0.01) of fracture healing. Blocking the NK1-receptor suppresses gene expression in and reduces biomechanical strength of healing bone. Therefore, we assume a potential therapeutic relevance of Substance P in cases of disturbed fracture healing.