Osteoarthritis (OA) is a degenerative arthritis disease marked by inflammation, pain, and cartilage deterioration. Elevated nitric oxide (NO) levels play a pivotal role in mediating OA-related inflammation and are found in abundance within OA joints. This study introduces a NO-scavenging hyaluronic acid conjugate (HA-NSc) bearing both lubrication and anti-inflammatory properties for the treatment of osteoarthritis. For this, a derivative of o-phenylenediamine (o-PD) with good NO-scavenging capability (NSc) is designed, synthesized and chemically conjugated to HA. Owing to the amphiphilicity, this as-synthesized HA-NSc conjugate formed self-assembled nanoparticles (HA-NSc NPs) under aqueous conditions. When treated with activated murine macrophage RAW 264.7 cells that produce high levels of NO, these nanoparticles effectively reduced intracellular NO concentrations and inflammatory cytokines. In an OA animal model, the HA-NSc NPs significantly alleviated pain and diminished the cartilage damage due to the combined lubricating property of HA and NO-scavenging ability of NSc. Overall, the results from the study suggest HA-NSc NPs as a dual-action therapeutic agent for the treatment of OA by alleviating pain, inflammation, and joint damage, and also positioning the HA-NSc NPs as a promising candidate for innovative treatment of OA.