<p>Retinal ganglion cell (RGC) degeneration is characterized by irreversible progression and a high risk of blindness. As a common pathological feature of various ocular diseases, including glaucoma and diabetic retinopathy (DR), RGC degeneration imposes a substantial burden on patients’ visual function. Current therapeutic strategies remain limited by their narrow therapeutic targets, insufficient neuroprotective efficacy, and challenges in clinical translation. Therefore, elucidating the core regulatory mechanisms underlying RGC degeneration is essential for the development of novel therapeutic strategies. Neuro-glial-immune interactions play a critical role in RGC degeneration and involve key participants such as resident retinal microglia, the complement system, circulating immune cells, astrocytes, and Müller cells, as well as dynamic crosstalk among these components. This review provides a comprehensive analysis of the mechanisms of neuroimmune interactions, potential therapeutic targets, and intervention strategies associated with RGC degeneration. Furthermore, it discusses current challenges and future directions, thereby providing a valuable reference for both basic research and the clinical translation of therapies for RGC-related blinding ocular diseases.</p> Graphical abstract <p></p>