The objective of this study is to investigate lncRNA FLG-AS1-mediated miR-380-3p/SOCS6 axis in inflammation, oxidative stress, and apoptosis of retinal epithelial cells in diabetic retinopathy (DR). Fasting blood was collected from 60 DR patients and 60 healthy controls. The Pearson correlation was used to analyze the correlation between the expression levels of FLG-AS1 and miR-380-3p in DR patients. qRT-PCR and/or Western blotting were used to detect the expression of FLG-AS1, miR-380-3p, and SOCS6. After gain of function of FLG-AS1 or SOCS6 or loss of function of miR-380-3p, high glucose (HG)-treated human retinal pigment epithelial ARPE-19 cells were subjected to TUNEL assessment of apoptosis. ELISA was performed to detect the expression levels of IL-1β, IL-6, and TNF-α in cell culture supernatant. DCFH-DA was used to detect the level of ROS in the cells. MDA and SOD assay kits were used to measure the activity of MDA and SOD in the cells. Dual-luciferase reporter assay was performed to verify the binding between miR-380-3p and FLG-AS1 or between miR-380-3p and SOCS6. Streptozotocin injections were used to induce diabetes in rats which were injected with FLG-AS1 overexpression lentiviral vectors in the eye. Twenty weeks later, retinal tissue was isolated and stained with hematoxylin-eosin or TUNEL. Compared to that in healthy controls, FLG-AS1 expression decreased 2.5-fold and miR-380-3p expression increased 2.6-fold in the serum of DR patients. The expression levels of FLG-AS1 and miR-380-3p were negatively correlated in DR patients (r = -0.3772, P = 0.003). Overexpression of FLG-AS1 reduced inflammation, oxidative stress, and apoptosis of HG-treated ARPE-19 cells and alleviated retinal injury in diabetic rats. FLG-AS1 promoted the expression of SOCS6 by targeting miR-380-3p. Inhibition of miR-380-3p or overexpression of SOCS6 reduced inflammation, oxidative stress, and apoptosis of HG-treated ARPE-19 cells. FLG-AS1 mitigates DR by regulating retinal epithelial cell inflammation, oxidative stress, and apoptosis via the miR-380-3p/SOCS6 axis.