Poly(p-coumaric acid) nanoparticles (PCA NPs) effectively alleviate temporomandibular joint osteoarthritis (TMJOA) by inhibiting chondrocyte ferroptosis. This study demonstrates that PCA NPs, synthesized from p-coumaric acid, exhibit potent antioxidant, anti-inflammatory, and ferroptosis-inhibiting properties, making them a promising therapeutic option for TMJOA. Compared to hyaluronic acid (HA), PCA NPs show superior long-term efficacy in reducing inflammation, oxidative stress, matrix degradation, and chondrocyte ferroptosis while promoting cell proliferation and matrix synthesis. In a rat model of TMJOA, intra-articular injection of PCA NPs significantly improved TMJ cartilage and subchondral bone repair. The mechanism of action involves the reduction of oxidative stress, inhibition of ferroptosis, and modulation of inflammatory responses. PCA NPs were characterized for size, stability, and antioxidant activity, showing a particle size of 118 nm, a zeta potential of -18.2 mV, and strong antioxidant properties. In vitro experiments confirmed the biocompatibility and cellular uptake of PCA NPs by chondrocytes. The study also revealed that PCA NPs effectively counteracted the effects of IL-1β, a key inflammatory factor in TMJOA, by reducing MMP3, MMP9, MMP13, and iNOS expression while increasing Collagen II and PCNA expression. In vivo experiments showed that PCA NPs significantly reduced subchondral bone destruction and improved cartilage repair, with the most significant improvements observed at 8 weeks post-treatment. Transcriptomic analysis indicated that PCA NPs modulate oxidative stress pathways and ferroptosis-related genes, highlighting their role in preventing cartilage degradation. PCA NPs also protected chondrocytes from ferroptosis by reducing iron overload, mitochondrial dysfunction, and lipid peroxidation. These findings suggest that PCA NPs are a promising therapeutic strategy for TMJOA due to their multifunctional properties in reducing inflammation, oxidative stress, and chondrocyte death.Poly(p-coumaric acid) nanoparticles (PCA NPs) effectively alleviate temporomandibular joint osteoarthritis (TMJOA) by inhibiting chondrocyte ferroptosis. This study demonstrates that PCA NPs, synthesized from p-coumaric acid, exhibit potent antioxidant, anti-inflammatory, and ferroptosis-inhibiting properties, making them a promising therapeutic option for TMJOA. Compared to hyaluronic acid (HA), PCA NPs show superior long-term efficacy in reducing inflammation, oxidative stress, matrix degradation, and chondrocyte ferroptosis while promoting cell proliferation and matrix synthesis. In a rat model of TMJOA, intra-articular injection of PCA NPs significantly improved TMJ cartilage and subchondral bone repair. The mechanism of action involves the reduction of oxidative stress, inhibition of ferroptosis, and modulation of inflammatory responses. PCA NPs were characterized for size, stability, and antioxidant activity, showing a particle size of 118 nm, a zeta potential of -18.2 mV, and strong antioxidant properties. In vitro experiments confirmed the biocompatibility and cellular uptake of PCA NPs by chondrocytes. The study also revealed that PCA NPs effectively counteracted the effects of IL-1β, a key inflammatory factor in TMJOA, by reducing MMP3, MMP9, MMP13, and iNOS expression while increasing Collagen II and PCNA expression. In vivo experiments showed that PCA NPs significantly reduced subchondral bone destruction and improved cartilage repair, with the most significant improvements observed at 8 weeks post-treatment. Transcriptomic analysis indicated that PCA NPs modulate oxidative stress pathways and ferroptosis-related genes, highlighting their role in preventing cartilage degradation. PCA NPs also protected chondrocytes from ferroptosis by reducing iron overload, mitochondrial dysfunction, and lipid peroxidation. These findings suggest that PCA NPs are a promising therapeutic strategy for TMJOA due to their multifunctional properties in reducing inflammation, oxidative stress, and chondrocyte death.