Background <p>Temporomandibular joint osteoarthritis (TMJ-OA) is a subtype of temporomandibular joint disorder characterised by synovial inflammation and cartilage degradation. Endoplasmic reticulum stress (ERS) plays a critical role in osteoarthritis pathophysiology. This study aimed to investigate the protective effects of platelet-rich plasma (PRP) on condylar chondrocytes, focusing on its potential to alleviate ERS and inhibit apoptosis, and evaluate the efficacy of PRP as a therapeutic strategy for TMJ-OA.</p> Methods <p>We conducted in vivo and in vitro experiments using transcriptome sequencing, RT-qPCR, and western blotting to examine the effects of PRP on the condylar chondrocytes. This study focused on ERS regulation and the IGF1R/PI3K/AKT signalling pathway. A clinical trial was performed to compare the therapeutic benefits of single and multiple PRP injections in patients (<i>n</i> = 32) with TMJ-OA.</p> Results <p>PRP effectively repaired cartilage damage in TMJ-OA by reducing ERS and inhibiting apoptosis via the IGF1R/PI3K/AKT axis. Both animal models and clinical trials have demonstrated that multiple PRP injections provide superior outcomes in condylar cartilage repair, pain relief, and functional improvement compared with those with a single injection.</p> Conclusions <p>PRP alleviates condylar chondrocyte ERS and inhibits apoptosis, contributing to the repair of cartilage damage in TMJ-OA. Multiple PRP injections are more effective than a single injection, supporting their use as promising therapeutic strategies for TMJ-OA management.</p> Trial registration <p>Chinese Clinical Trial Registry (registration ID ChiCTR1900023013).</p>