Background and aims: Lichen planus (LP) and discoid lupus erythematosus (DLE) are two relatively common mucocutaneous lesions whose clinical and histopathological features overlap in some cases. The present study aimed to distinguish between these two lesions histopathologically in order to treat them more accurately. Methods: In a cross-sectional descriptive-analytical study, 29 and 48 microscopic slides of skin samples of DLE and LP, respectively, were examined in the pathology archive of Al-Zahra hospital of Isfahan from 2008 to 2018. The slides prepared by hematoxylin-eosin staining were examined simultaneously and blindly by three pathologists with a light microscope and compared according to certain histopathological criteria. Then obtained data were analyzed by SPSS version 24 using chi-square, Fisher’s exact, Mann-Whitney, and t tests (P<0.05). Results: Based on the findings, the presence of hyperparakeratosis with superficial hyperorthokeratosis, epithelial atrophy, deep perivascular infiltration, presence of edema in the papillary dermis, presence of plasma cells with lymphohistiocytes in inflammatory infiltration, and presence of mucin in the dermis were significantly higher in DLE than in LP (P<0.05). On the other hand, the intensity of lichenoid infiltration, presence of saw tooth hyperplasia of rete ridges, presence of cleft between the epithelium and connective tissue, spongiosis, hyperorthokeratosis alone, and wedge-shaped hypergranulosis were significantly higher in LP than in DLE (P<0.05). Conclusion: Perieccrine and perifollicular inflammation, presence of Civatte bodies (CBs), abundance of fibrosis, presence of pale keratinocytes, and presence of pseudoepitheliomatous hyperplasia were not the criteria for differential diagnosis of LP and DLE.