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Amyloid‐beta (Aβ) oligomer is known to contribute to the pathophysiology of age‐related macular degeneration. Herein, we aimed to elucidate the in vivo and in vitro effects of Aβ1‐42 application on retinal morphology in rats. Our in vivo studies revealed that intracerebroventricular administration of Aβ1‐42 oligomer caused dysmorphological changes in both retinal ganglion cells and retinal pigment epithelium. In addition, in vitro studies revealed that ARPE‐19 cells following Aβ1‐42 oligomer application had decreased viability along with apoptosis and decreased expression of the tight junction proteins, increased expression of both phosphor‐AKT and phosphor‐GSK3β and decreased expression of both SIRT1 and β‐catenin. Application of conditioned medium (CM) obtained from mesenchymal stem cells (MSC) protected against Aβ1‐42 oligomer‐induced retinal pathology in both rats and ARPE‐19 cells. In order to explore the potential role of peptides secreted from the MSCs, we applied mass spectrometry to compare the peptidomics profiles of the MSC‐CM. Gene ontology enrichment analysis and String analysis were performed to explore the differentially expressed peptides by predicting the functions of their precursor proteins. Bioinformatics analysis showed that 3‐8 out of 155–163 proteins in the MSC‐CM maybe associated with SIRT1/pAKT/pGSK3β/β‐catenin, tight junction proteins, and apoptosis pathway. In particular, the secretomes information on the MSC‐CM may be helpful for the prevention and treatment of retinal pathology in age‐related macular degeneration., Aβ‐induced cell apoptosis may through inhibits SIRT1, enhanced AKT and GSK3β phosphorylation, and suppressed β‐catenin expression, and disrupted tight junction protein expression. It is well known that β‐catenin could maintain tight junction protein (such as ZO‐1 and occludin) expression and inhibit apoptosis. Conditioned medium (N‐CM or H‐CM) from mesenchymal stem cells under normoxic or hypoxic culture environment could reverse the Aβ‐induced apoptosis and tight junction protein disruption via APOC3, APOA1, KNG1, PSAP, HSP90B1, ACLY, YWHAE, and H2AFX from N‐CM, and CD44, PSMA1, and CTTN from H‐CM, which are all related to SIRT1/pAKT/pGSK3β/β‐catenin signaling pathway.