Nonexudative age-related macular degeneration (dry AMD) is characterized by the accumulation of scattered drusen and progressive atrophy of retinal pigment epithelial (RPE) cells, which leads to the degeneration of photoreceptor cells and a decrease in central vision. MiR-21-5p plays an important role in a variety of ophthalmological diseases, such as diabetic retinopathy, glaucoma, pterygium, and laser-induced choroidal neovascularization. Therefore, we speculate that miR-21-5p may be involved in the regulation of RPE cell damage in AMD. Rats with NaIO3-induced dry AMD received an intravitreal injection of miR-21-5p agomir or antagomir. Optical coherence tomography (OCT), fundus, histopathological studies and biochemical markers were assessed. We observed high expression of miR-21-5p in NaIO3-treated rats. Intravitreal injection of the miR-21-5p agomir significantly accelerated NaIO3-induced RPE damage. This response was ameliorated by the pretreatment of dry AMD model rats with the miR-21-5p antagomir. Moreover, miR-21-5p regulated CoCl2-induced RPE cell necroptosis in vitro, as shown by flow cytometry and immunostaining for receptor interacting protein kinase 3 (RIP3) and HMGB1. Specifically, miR-21-5p bound to the Pellino1 (Peli1) 3’ UTR to silence its expression. Peli1 overexpression effectively prevented CoCl2-induced RPE cell necroptosis. These findings show the potential for miRNA-based therapy in the treatment of dry AMD.