Subretinal hemorrhage-induced neurotoxicity is a key cause of vision loss in age-related macular degeneration (AMD). The purpose of this study is to investigate the effects of Propofol on neurotoxicity. Oxygen glucose deprivation (OGD) was used to establish in vitro subretinal hemorrhage model. Gene expression was determined using reverse transcription-quantitative polymerase chain reaction and western blot. Cytokine release was determined using enzyme-linked immunosorbent assay. The interaction between sirtuin 6 (SIRT6) and NLR family pyrin domain containing 3 (NLRP3) was detected using co-immunoprecipitation assay. Cellular function was determined using cell counting kit-8 assay, lactate dehydrogenase assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Propofol suppressed the inflammatory response induced by OGD. Moreover, Propofol inhibited the neurotoxicity and pyroptosis of photoreceptors. Propofol mediated the overexpression of SIRT6, which was downregulated in AMD. Inhibition of SIRT6 alleviated its deacetylation of NLRP3. Additionally, SIRT6 deficiency antagonized the effects of Propofol and promoted the neurotoxicity and pyroptosis of photoreceptors. Taken together, Propofol protects against subretinal hemorrhage-induced neurotoxicity and pyroptosis of photoreceptors via promoting SIRT6-mediated deacetylation of NLRP3.