Poly (ADP-ribose) polymerase 1 (PARP1) plays an irreplaceable role in the progression of diabetic retinopathy (DR). The m6A methylation in mRNA controls gene expression under various physiological and pathological conditions. However, effects of m6A methylation on PARP1 expression and DR progression at molecular level have not been documented. This study shows that the levels of PARP1, inflammatory factors, and fibrosis markers were significantly upregulated via evaluation by real-time PCR, western blotting, and immunofluorescence in both in vivo and in vitro experiments. EdU, CCK8, and apoptosis assays demonstrate that knockdown of PARP1 not only significantly improved the vitality of hRMECs (human retinal microvascular endothelial cells) even under high glucose conditions but also prevented glucose-induced inflammation, fibrosis, and angiogenesis in vivo. Mechanistically, dot blot, RNA pull-down, and immunoblots were implemented to explore the mechanism of m6A-mediated PARP1 stability and function. PARP1 is identified as a target of YTHDF2-mediated m6A modification. Overexpression of YTHDF2 substantially suppressed PARP1 mRNA m6A modification and inhibited its mRNA expression. Collectively, it has been demonstrated that PARP1 is frequently upregulated in human retinas and contributes to DR progression, and that YTHDF2-mediated m6A modification epigenetically regulates diabetes-induced PARP1 expression. Findings from this work may engender therapeutic targets for treating diabetic retinopathy.