Retinal vascular diseases (RVDs) are leading causes of vision impairment and blindness, often associated with systemic diseases such as diabetes and hypertension. Despite treatment advancements, managing RVDs, particularly retinal vein occlusion (RVO), remains challenging due to the lack of a definitive cure and reliance on controlling complications. Microglia, the retina’s resident immune cells, play a crucial role in maintaining retinal health, regulating inflammation, and modulating angiogenesis. In pathological conditions, microglia adopt heterogeneous and context-dependent activation states, contributing to both inflammatory injury and vascular repair. Studies suggest that modulating microglial activation and their secreted cytokines may provide novel therapeutic strategies for RVDs. This review examines the role of microglia in RVDs and their potential as therapeutic targets, exploring strategies such as inhibiting microglial activation, regulating pro-angiogenic factor secretion, and targeting specific signaling pathways. Future research should focus on understanding the specific roles of microglial subtypes, their contributions to disease progression, and developing targeted therapies for early diagnosis and treatment of RVDs.

With the acceleration of global aging, the incidence of retinal vein occlusion (RVO) has risen markedly. Its pathogenic mechanisms are closely linked to iron dyshomeostasis and microglial polarization and age-related degenerative changes in retinal microvessels. We systematically summarize the regulatory mechanisms of ferroptosis—an iron-dependent, lipid peroxidation-driven form of cell death, and elucidate the central pathway by which iron overload exacerbates retinal injury through the synergy of hypoxia-reoxygenation (H/R). Specifically, iron metabolic imbalance catalyzes the production of reactive oxygen species (ROS) via the Fenton reaction, which drives the polarization of microglia toward the proinflammatory M1 phenotype and activates the acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation cascade. This review proposes novel insights for combinatorial therapeutic strategies targeting key ferroptotic pathways (e.g., the SLC7A11/GPX4 axis) and modulating microglial polarization, while also addressing the translational challenges associated with iron chelators (deferoxamine), lipid peroxidation inhibitors (liproxstatin-1), and targeted delivery systems for RVO.