When compared with healthy controls, NOTCH signaling was markedly elevated in the lens capsules of eyes with pseudoexfoliation syndrome (PXF) but not in those with pseudoexfoliation glaucoma (PXG). NOTCH signaling had neuroprotective properties, and it was linked to neurodegenerative illnesses characterized by protein aggregation, such as Alzheimer’s disease. NOTCH molecular expression in the lens capsules of patients with PXF, PXG, primary open-angle glaucoma (POAG), and healthy controls were investigated because PXG was likewise a protein aggregation illness linked with neurological degeneration. Anterior lens capsules were taken from 106 cataract surgery patients (27 PXF, 24 PXG, 22 POAG, and 33 controls). A quantitative reverse transcription-polymerase chain reaction was used to profile the tissue’s gene expression for NOTCH pathway molecules (ligands, receptors, and downstream target genes). Protein analysis utilizing dot-blot or immunostaining techniques corroborated the outcomes. There were no significant differences in demographic features between the 2 groups. The PXF group had a more than 14-fold increase in NOTCH4 receptor expression compared to the controls. Similarly, when compared with controls, the Delta-like 3 and Delta-like 4 ligands were considerably higher in the PXF group (P<0.05). In PXF lens capsules, expression of downstream targets HES3, HES5, and HEY1 was considerably increased (P<0.005), demonstrating a higher activity of NOTCH signaling in the cohort. The gene expression profile was also confirmed by immunostaining. The fact that NOTCH signaling was significantly increased in the lens capsule of PXF patients but not in PXG or POAG patients implied that NOTCH might have played a protective function in glaucoma development.