Bone and joint infections (BJIs) are difficult to treat, necessitating antimicrobial therapy at high doses for an extended period of time, in some cases different from our local guidelines. As a consequence of the rise in antimicrobial-resistant organisms, drugs that were previously reserved for last-line defense are now being used as first line treatment, and the pill burden and adverse effects on patients are leading to nonadherence, encouraging antimicrobial resistance (AMR) to these last-resort medicines. Nanodrug delivery is the field of pharmaceutical sciences and drug delivery which combines nanotechnology with chemotherapy and/or diagnostics to improve treatment and diagnostic outcomes by targeting specific cells or tissues affected. Delivery systems based on lipids, polymers, metals, and sugars have been used in an attempt to provide a way around AMR. This technology has the potential to improve drug delivery by targeting the site of infection and using the appropriate amount of antibiotics to treat BJIs caused by highly resistant organisms. This Review aims to provide an in-depth examination of various nanodrug delivery systems used to target the causative agents in BJI.