Background <p>Disruption of the retinoid (visual) cycle causes all-<i>trans</i>-retinal (atRAL) to accumulate in photoreceptors and retinal pigment epithelium (RPE), contributing to Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (dAMD). Yet, the mechanisms underlying atRAL-induced RPE degeneration are not well understood. Here, we explored whether ferroptosis, a form of regulated cell death marked by iron-dependent lipid peroxidation, mediated RPE damage by atRAL.</p> Methods <p>Cell and animal models of STGD1 and dAMD were established using ARPE-19 cells loaded with atRAL and <i>Abca4</i>^{<i>−/−</i>}<i>Rdh8</i>^{<i>−/−</i>} mice subjected to light exposure. Cell viability and morphology, mitochondrial morphology, ferrous iron (Fe²⁺) levels, reactive oxygen species (ROS) production, lipid peroxidation, and ferroptosis-related gene and protein expression were assessed using MTS assay, inverted and confocal microscopy, fluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, respectively. The conditions of mouse retina were evaluated by electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunofluorescence labeling.</p> Results <p>atRAL triggered ferroptosis of ARPE-19 cells through Fe²⁺ accumulation, ROS generation, lipid peroxidation, mitochondrial damage, and abnormal expression of typical ferroptosis-related genes and proteins. These effects were capable of being alleviated by treatment with ferrostatin-1 (Fer-1), a potent ferroptosis inhibitor. Moreover, ferroptosis was clearly observed in the RPE of light-exposed <i>Abca4</i>^{<i>−/−</i>}<i>Rdh8</i>^{<i>−/−</i>} mice that showed rapid and excessive accumulation of atRAL in the retina. Notably, intraperitoneal administration of Fer-1 effectively mitigated the degeneration of the RPE and photoreceptors and significantly ameliorated retinal function in <i>Abca4</i>^{<i>−/−</i>}<i>Rdh8</i>^{<i>−/−</i>} mice following light exposure.</p> Conclusions <p>Ferroptosis plays a critical role in RPE damage by atRAL. Inhibition of ferroptosis by Fer-1 may enhance RPE cell survival and prevent subsequent photoreceptor degeneration in STGD1 and dAMD.</p>