A bio‐guided isolation was applied to the Vietnamese lichen Roccella montagnei based on alpha‐glucosidase inhibition. Six compounds were isolated and structurally elucidated, including a new ortho depside, montagneside A (1), together with five known compounds, sekikaic acid (2), lanost‐7‐en‐3β‐ol (3), ethyl orsellinate (4), D‐montagnetol (5), and D‐erythrin (6). Their chemical structures were identified by extensive 1D and 2D NMR analysis, high‐resolution mass spectroscopy, and comparisons with those reported in the literature. D‐Erythrin (6), a major component, was selected for further modification using Smiles rearrangement. Three erythritol derivatives 6a‐6c were synthesized. Compounds 1‐3, 6, and 6a‐6c were evaluated for alpha‐glucosidase inhibition. Compounds 2 and 6a‐6c showed significant alpha‐glucosidase inhibition with IC50 values ranging from 7.9 to 149 µM, respectively. Molecular docking was applied to the most active compound 6a to clarify the inhibitory mechanism.