Type 2 diabetes mellitus (T2DM), driven by progressive pancreatic β-cell dysfunction and impaired insulin secretion, is a major global health burden, and new antidiabetic leads with β-cell-protective potential are needed. The sulfonylurea receptor 1 (SUR1), which gates ATP-sensitive potassium channels controlling pancreatic β-cell insulin release, is a validated but still underexploited antidiabetic drug target. Natural products derived from lichens and their associated endolichenic fungi (ELF) offer promising sources of bioactive secondary metabolites with therapeutic potential. This study investigated 20 lichen- and endolichenic fungal-derived compounds against pancreatic SUR1 using integrated molecular docking, biochemical assays, and pancreatic β-cell models. Molecular docking revealed that anthracen-9-one (from Ramalina conduplicans) and 2-methylresorcinol from Parmotrema reticulatum exhibited superior binding affinities (total energy: -96.64 and − 67.93 kcal/mol, respectively) compared to glibenclamide (-85.02 kcal/mol). In alloxan-induced RIN-5 F pancreatic β-cell lines, the chloroform extract of endolichenic fungus Xylaria curta (XCC) demonstrated potent cytoprotection, with 95.53% cell viability at 25 µg/mL. Treatment with XCC dose-dependently inhibited α-amylase activity (51% at 50 µg/mL) and enhanced glucose utilization (125% at 50 µg/mL), while suppressing alloxan-induced apoptosis. Mechanistically, active compounds stabilized key regulatory residues (THR-107, GLN-339, SER-336) in the SUR1 binding pocket, preserving insulin secretion capacity. These findings establish lichenic metabolites, particularly from ELF, contributing to the UN Sustainable Development Goal 3 (SDG-3) for Good Health and Well-being, specifically addressing the global burden of diabetes mellitus. Consequently, DNA sequences of X. curta and M. fragilis were deposited in NCBI with accession numbers for reference and future studies. Keywords: Anthracen-9-one · Diabetes mellitus · Endolichenic fungi · Lichens · Mucor fragilis · Parmotrema reticulatum · Ramalina conduplicans.