Bacterial biofilms create a challenge in the treatment of prosthetic joint infection (PJI), and failure to eradicate biofilms is often implicated in the high rates of recurrence. In this study, we aimed to compare the effectiveness of a novel nanoparticle ultrasonication technology on Staphylococcus aureus biofilm eradication compared to commonly used orthopedic irrigation solutions. Twenty-four sterile, titanium alloy discs were inoculated with a standardized concentration of methicillin-resistant S. aureus and cultured for seven days to allow for biofilm formation. Discs were then treated with either ultrasonicated nanoparticle therapy or irrigation with chlorhexidine gluconate, povidone-iodine or normal saline. The remaining bacteria on each surface was subsequently plated for colony-forming units of S. aureus. Bacterial eradication was reported as a decrease in CFUs relative to the control group. Mann-Whitney U tests were used to compare between groups. Treatment with ultrasonicated nanoparticles resulted in a significant mean decrease in CFUs of 99.3% compared to controls (p < 0.0001). Irrigation with povidone-iodine also resulted in a significant 77.5% reduction in CFUs compared to controls (p < 0.0001). Comparisons between ultrasonicated nanoparticles and povidone-iodine demonstrated a significantly higher reduction in bacterial CFUs in the nanoparticle group (p < 0.0001). Ultrasonicated nanoparticle were superior to commonly used bactericidal irrigation solutions in the eradication of S. aureus from a titanium surface. Future clinical studies are warranted to evaluate this ultrsonication technology in the treatment of PJI.