This study aimed to identify dysregulated proteins, signaling pathways, and biological processes on the ocular surface of patients with Sjögren’s syndrome dry eye (SSDE) disease. Non-targeted proteomic analysis of Schirmer strip (ScS) samples from 12 SSDE patients compared to 6 healthy subjects (HS) revealed 111 dysregulated proteins. It showed significant proteome segregation between SSDE patients and HS, revealing alterations in the cytoskeleton, cell junctions, and cellular metabolism, as well as increased apoptosis and oxidative stress and reduced levels of CXCL17 and PRDX6 in SSDE.