Amyloid-beta (A beta) is thought to be a critical pathologic factor of retinal pigment epithelium (RPE) degeneration in age-related macular degeneration (AMD). A beta induces inflammatory responses in RPE cells and recent studies demonstrate the N6-methyladenosine (m6A) regulatory role in RPE cell inflammation. m6A is a reversible epigenetic posttranslational modification, but its relationship with A beta-induced RPE degeneration is yet to be thoroughly investigated. The present study explored the role and mechanism of m6A in A beta-induced RPE degeneration model. This model was induced via intravitreally injecting oligomeric A beta and the morphology of its retina was analyzed. One of m6A demethylases, the fat mass and obesity-associated (FTO) gene expression, was assessed. An m6A-messenger RNA (mRNA) epitranscriptomic microarray was employed for further bioinformatic analyses. It was confirmed that A beta induced FTO upregulation within the RPE. Hypopigmentation alterations and structural disorganization were observed in A beta-treated eyes, and inhibition of FTO exacerbated retinal degeneration and RPE impairment. Moreover, the m6A-mRNA epitranscriptomic microarray suggested that protein kinase A (PKA) was a target of FTO, and the PKA/cyclic AMP-responsive element binding (CREB) signaling pathway was involved in A beta-induced RPE degeneration. m6A-RNA binding protein immunoprecipitation confirmed that FTO demethylated PKA within the RPE cells of A beta-treated eyes. Altered expression of PKA and its downstream targets (CREB and brain-derived neurotrophic factor) was confirmed by quantitative reverse-transcription polymerase chain reaction and Western blot analyses. Hence, this study's findings shed light on FTO-mediated m6A modification in A beta-induced RPE degeneration and indicate potential therapeutic targets for AMD.