Background: Antibiotic-loaded bone cement (ALBC) is widely used for local antibiotic delivery in joint arthroplasty to prevent and treat prosthetic joint infections (PJIs). In this study, we evaluated the efficacy of cemented Kirschner (K)-wires coated with various ALBC formulations using a Galleria mellonella infection model against multidrug-resistant (MDR) Staphylococcus aureus and Enterococcus faecalis. Methods: We tested commercially available bone cements, including gentamicin-only formulations (PALACOS R+G) and dual-antibiotic formulations, combining gentamicin with either clindamycin (COPAL G+C) or vancomycin (COPAL G+V), alongside an antibiotic-free control (PALACOS R). In vitro assays—including minimum inhibitory/bactericidal concentration (MIC/MBC) determination, antibiotic release kinetics, agar diffusion, and antibiofilm evaluations—demonstrated effective antibiotic release and significant antimicrobial activity against both planktonic and biofilm-associated bacteria. Results: In vivo, ALBC-coated K-wires were well tolerated in G. mellonella and significantly protected the larvae from S. aureus infection compared to controls. Notably, dual-antibiotic formulations provided superior protection, correlating with substantial reductions in bacterial colonisation on implant surfaces and in surrounding tissues. Conclusions: These findings support the utility of the G. mellonella model as a high-throughput, cost-effective platform for the preclinical evaluation of antimicrobial strategies to prevent and treat PJIs and further demonstrate the effectiveness of dual-loaded ALBC against multidrug-resistant bacteria.