Despite recent advances in medical technology, treatment of chronic osteomyelitis in the small joint of the hand remains challenging. Here, we exploited hybrid biodegradable hydrogel/microparticle/polycaprolactone (PCL) sacs for finger joint interpositional arthroplasty via electrospraying and rotational molding techniques. Degradable Pluronic F127, poly(lactic-co-glycolic acid) (PLGA), and PCL were starting materials for the hydrogels, microparticles, and sac, respectively. Vancomycin, ceftazidime, and lidocaine were the embedded pharmaceuticals. The in vitro and in vivo drug release behaviors of hybrid drug-eluting sacs were assessed. The empirical outcomes show that the size distribution of the electrosprayed vancomycin/ceftazidime/lidocaine PLGA microparticles was 8.25 ± 3.35 μm. Biodegradable PCL sacs offered sustainable and effective release of vancomycin, ceftazidime, and lidocaine, respectively, after 30, 16, and 11 days in vitro. The sacs also discharged high levels of anti-microbial agents for 56 days and analgesics for 14 days in a rabbit knee joint model. The blood urea nitrogen (creatinine) levels remained normal at various time points: 16.5 ± 2.5 mg/dL (0.85 ± 0.24 mg/dL), 20.0 ± 1.4 mg/dL (1.0 ± 0.16 mg/dL), 19.3 ± 2.4 mg/dL (1.13 ± 0.15 mg/dL), and 20.0 ± 2.16 mg/dL (1.0 ± 0.16 mg/dL) at days 7, 14, 21, and 35, respectively. The empirical outcomes of this study suggested that the hybrid biodegradable drug-eluting sacs with extended liberation of pharmaceuticals may find applications in the small joints for post-operative pain relief and infection control.