<p>Despite the substantial progress in drug discovery and precision therapeutics, the predictive power of current ocular safety assessments remains limited owing to the lack of human experimental models. Conventional two-dimensional cell cultures lack the complex laminar organization, multicellular interactions, and functional electrophysiological properties of the human retina. Additionally, animal models frequently exhibit species-specific differences in retinal development, metabolism, and stress responses that hinder translational accuracy. Human induced pluripotent stem cell-derived retinal organoids are transformative microphysiological platforms that recapitulate key aspects of the human retinal architecture, including photoreceptor differentiation, synaptic connectivity, and neuronal functionality within a three-dimensional and human-derived context. In addition to structural resemblance, these systems enable multidimensional and mechanism-related toxicity assessments of oxidative stress, mitochondrial dysfunction, lysosomal impairment, ferroptotic signaling, synaptic dysregulation, and adaptive cytoprotective pathways. Therefore, retinal organoids can be incorporated into quantitative and regulatory toxicological frameworks using concentration–response modeling, benchmark dose derivation, and adverse outcome pathway mapping. Notably, these models identify the reactive oxygen species-mitochondria-lysosome axis as a central vulnerability hub that mechanistically links diverse exposure modalities, including small-molecule drugs, biologics, gene therapies, and nanomaterials, to photoreceptor degeneration. Ongoing advances in maturation, vascular-like integration, microfluidic coupling, and interline reproducibility have further enhanced their translational value. Collectively, retinal organoids are redefining ocular safety assessments by shifting the paradigm from hazard identification to predictive, mechanism-based, and human toxicology.</p>