Chronic osteomyelitis requires effective localized antimicrobial delivery while avoiding systemic organ toxicity. This study evaluated and compared the systemic biocompatibility and safety of locally implanted vancomycin-loaded polycaprolactone (VAN/PCL) versus curcumin-loaded polycaprolactone (CUR/PCL) nanocomposites in a rabbit model of experimental Staphylococcus aureus osteomyelitis. Adult male New Zealand white rabbits with induced femoral osteomyelitis underwent surgical debridement at 14 days post-inoculation (14 dpi/0 dpt) and were allocated into three groups: VAN/PCL, CUR/PCL, or untreated debrided control. Animals were monitored longitudinally over a 60-day post-treatment period. Blood samples were collected at baseline (0 dpi/14 dpt) and at 7, 15, 30, 45, and 60 dpt (corresponding to 21, 29, 44, 59, and 74 dpi). Hematological parameters and serum biomarkers (BUN, SCR, ALT, AST, ALP) were quantified. Osteomyelitis induction elicited systemic leukocytosis and neutrophilia before intervention (p < 0.05 vs. baseline). Following implantation, leukocyte and neutrophil counts in both groups declined progressively toward physiological baseline by 45–60 dpt (59–74 dpi). Serum renal biomarkers (BUN and SCR) and ALP remained within physiological limits in both cohorts across all time points. While transaminase levels remained stable in the CUR/PCL group throughout the study, the VAN/PCL cohort exhibited a transient elevation in AST and ALT at 7 dpt (21 dpi) compared to both its baseline (p < 0.05) and the CUR/PCL group (p < 0.05). These enzymatic elevations in the VAN/PCL group resolved progressively, returning completely to baseline physiological ranges by 60 dpt (74 dpi) (p > 0.05). Both nanocomposites demonstrated acceptable systemic tolerability. While VAN/PCL was associated with transient hepatic transaminase elevations, both formulations showed progressive resolution of inflammatory markers and normalization of hepatorenal indices by 60 dpt (74 dpi). These findings reflect whole-formulation clinical pathology profiles; future histopathological evaluations are required to confirm definitive microscopic tissue safety.