Common antibiotic therapies to treat bacterial infections are associated with systemic side effects and the development of resistance, directly connected to duration and dosage. Local drug delivery systems (DDSs) offer an alternative by localising antibiotics and thereby limiting their side effects while reducing the dosage necessary. A biodegradable polyester polycaprolactone (PCL)-based DDS was thus produced, containing various clinically relevant drugs. It was shown that the incorporation of four distinct antibiotic classes (amoxicillin, doxycycline, metronidazole and rifampicin), with very high mass fractions ranging up to 20 wt%, was feasible within the PCL matrix. This DDS showed the capacity for effective and sustained release. The release kinetics over 14 days were proven, showing a significant decrease in cytotoxicity with smooth muscle cells as well as an antibacterial effect on (1) aerobic, (2) anaerobic, (3) Gram-positive and (4) Gram-negative pathogens in vitro. The DDS demonstrated a markedly diminished cytotoxic impact owing to sustained release in comparison to pure antibiotics, while simultaneously maintaining their antibacterial efficacy. In conclusion, DDSs are a more tolerable form of antibiotics administration due to the hydrophobic PCL matrix causing a slower diffusion-controlled release, proven as a release mechanism via the Peppa-Sahlin model.