Thyroid hormone (TH) signaling is essential for cell proliferation, differentiation, and metabolic homeostasis. In the retina, TH signaling regulates retinal development, cone opsin expression, and photoreceptor viability. Suppressing TH signaling protects photoreceptors in mouse models of retinal degeneration whereas excessive TH signaling induces photoreceptor degeneration in mice. This work examined stress responses in the mouse retina after stimulation of TH signaling. C57BL/6 and Nrl−/− mice received triiodothyronine (T3, 0.5 and 1.5 μg/mouse/day, s.c.) for 15 or 5 days, respectively, starting on postnatal day 10, and were then analyzed for retinal stress responses/oxidative damage and mitochondrial function. Treatment with T3 induced oxidative damage and activation of Müller cells and microglia in the retina. Moreover, treatment with T3 reduced mitochondrial respiration activity and ATP production in the retina. This work demonstrates the detrimental effect of excessive TH signaling on retinal homeostasis and provides insight into the mechanisms underlying excessive TH signaling-induced retinal degeneration.