Infective endocarditis (IE) has been recognized as a biofilm-related disease caused by pathogenic microorganisms, such as bacteria and fungi that invade and damage the heart valves and endocardium. There are many difficulties and challenges in the antimicrobial treatment of IE, including multi-drug resistant pathogens, large dose of drug administration with following side effects, and poor prognosis. For the past few years, the development of nanotechnology has promoted the use of nanoparticles as antimicrobial nano-pharmaceuticals or novel drug delivery systems (NDDS) in antimicrobial therapy for chronic infections and biofilm-related infectious disease as these molecules exhibit several advantages. Therefore, nanoparticles have a potential role to play in solving problems in the treatment of IE, including improving antimicrobial activity, increasing drug bioavailability, minimizing frequency of drug administration, and preventing side effects. In this article, we review the latest advances in nanoparticles against drug-resistant bacteria in biofilm and recommends nanoparticles as an alternative strategy to the antibiotic treatment of IE.