Autologous blood centrifugation produces various forms of platelet concentrates widely used in tissue regenerative therapies due to their high concentrations of growth factors and abundance of autologous cells. Advanced Platelet-Rich Fibrin (A-PRF), introduced as a low-speed centrifugation product, contains an even higher concentration of growth factors, a greater number of cells, and a looser fibrin clot structure compared to previous Leukocyte and Platelet-Rich Fibrin (L-PRF). This study aims to assess the potential of A-PRF as a local delivery system for antibiotics. Different concentrations (0.5 mg/mL, 0.25 mg/mL, and 0.125 mg/mL) of injectable amoxicillin (AMX) and metronidazole (MTZ) were preliminarily tested for their impact on A-PRF clot formation, with 0.5 mg/mL selected for subsequent experiments. Blood samples from healthy volunteers were supplemented with antibiotics and centrifuged to form clots. Antibiotic-enriched A-PRF clots were immersed in phosphate-buffered saline (1x PBS) and analyzed at 24 h, 72 h, 7 days, and 14 days. AMX showed a consistent release (mean: 19.9 ± 4.8 ng/mL at 24 h) over 14 days, while MTZ demonstrated greater variability (mean: 12.8 ± 4.5 ng/mL at 24 h). AMX release remained constant over the 14-day period, with no significant variations among patients. In contrast, MTZ displayed a progressively lower release over time. Microbiological analysis revealed bacterial growth inhibition zones for