Azithromycin (AZT), a macrolide antibiotic, has recently been explored as an injection therapy for osteoarthritis. However, its instability and poor solubility limit its effect due to an insufficient quantity and duration at the target sites. To address these challenges, this study developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for AZT delivery, which were subsequently incorporated into a thermoresponsive injectable hydrogel suitable for intra-articular administration. The formulation was developed using a Quality by Design (QbD) approach, focusing on two steps: (i) preparation of AZT-PLGA NPs and (ii) loading the NPs into a poloxamer-based hydrogel. Critical material attributes (AZT, PLGA, surfactants) were evaluated for their impacts on the critical quality attributes (CQAs) of the NP formulation (size distribution and encapsulation efficiency). The optimized AZT-PLGA NPs exhibited a mean particle size of ~ 150 nm and a PDI of < 0.2, ensuring uniformity and stability. Secondly, these NPs were then embedded into a novel thermoresponsive hydrogel. The effects of NPs, hyaluronic acid, and mannitol on physical appearance, thermal sensitivity, the rheology (shear-thinning and thixotropic), pH, and sustained release properties of the final formulation were systematically investigated. Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analyses revealed interactions between AZT and PLGA, which, while not affecting the drug assay, enhanced the structural integrity and modified the thermal properties of the final product. Using QbD principles, a risk-based assessment was proposed for future drug development. This study introduced a novel thermoresponsive injectable hydrogel for the intra-articular delivery of AZT using PLGA nanoparticles.