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After retinal detachment (RD), the induction of autophagy protects photoreceptors (PR) from apoptotic cell death. The cytoplasmic high-mobility group box 1 (HMGB1) promotes autophagy. We previously demonstrated that the deletion of HMGB1 from rod PRs results in a more rapid death of these cells after RD. In this work, we tested the hypothesis that the lack of HMGB1 accelerates PR death after RD due to the reduced activation of protective autophagy in the retina after RD. The injection of 1% hyaluronic acid into the subretinal space was