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There remains a gap in our understanding of MGCs' responses to photoreceptor degeneration towards finding therapies. The study explores how an inhibition of store\u2010operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE) and its major component, Orai1 channel, in MGCs protects photoreceptors from degeneration. The study revealed increased Orai1 expression in the MGCs of retinal degeneration 10 (<jats:italic>rd10<\/jats:italic>) mice. Enhanced expression of oxidative stress markers was confirmed as a crucial pathological mechanism in <jats:italic>rd10<\/jats:italic> retina. Inducing oxidative stress in rat MGCs resulted in increasing SOCE and Ca<jats:sup>2+<\/jats:sup> release\u2010activated Ca<jats:sup>2+<\/jats:sup> (CRAC) currents. SOCE inhibition by 2\u2010Aminoethoxydiphenyl borate (2\u2010APB) protected photoreceptors in degenerated retinas. Finally, molecular simulations proved the structural and dynamical features of 2\u2010APB to the target structure Orai1. 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