Infections are a major complication of open fractures and fracture fixation. In this study, an innovative bioactive medical device was used to experimentally treat MRSE-induced osteomyelitis in rabbit tibia. This paper investigates the clinical significance of inflammatory biomarkers (NLR, PLR, MLR and PMR), SII and IL-6 and assesses their role in the development of osteomyelitis. The main objective is to identify the utility of hematological reports derived from neutrophils, leukocytes, monocytes and platelets in the evolution of implant-related osteomyelitis and the estimation of treatment efficiency. In particular, this study compares the response of these inflammatory markers to different treatments in the presence or absence of bioactive materials and/or topical antibiotics over time. The analysis of the threads showed that NLR, PLR and SII had high values in the acute phase of the disease, so that after chronicization, they decrease. The animals treated with vancomycin nano-functionalized peptide-enriched silk fibroin-coated implants showed lower levels of inflammatory biomarkers compared to the other groups (empty implants and peptide-enriched silk fibroin-coated implants). NLR, PLR and SII, complemented by IL-6 can be used as fairly accurate biomarkers for the diagnosis of osteomyelitis.