The nervous and immune systems go hand in hand in causing inflammation and pain. However, the two are not mutually exclusive. While some diseases cause inflammation, others are caused by it. Macrophages play an important role in modulating inflammation to trigger neuropathic pain. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan that has a well-known ability to bind with the cluster of differentiation 44 (CD44) receptor on classically activated M1 macrophages. Resolving inflammation by varying the molecular weight of HA is a debated concept. HA-based drug delivery nanosystems such as nanohydrogels and nanoemulsions, targeting macrophages can be used to relieve pain and inflammation by loading antinociceptive drugs and enhancing the effect of anti-inflammatory drugs. This review will discuss the ongoing research on HA-based drug delivery nanosystems regarding their antinociceptive and anti-inflammatory effects.