The keratinocytes actively participate in the cutaneous immune responses. Dysregulation and abnormal expression of inflammatory mediators or their receptors in keratinocytes are relevant to the pathogenesis of chronic inflammatory skin diseases. The mechanism of long‐lasting inflammatory processes is related with the activation of nuclear factor (NF)‐κB and mitogen‐activated protein kinase (MAPK), which play a crucial role in the immune responses. There are potential interaction points between these two pathways. The aim of this study is to investigate the differences in expression levels and distributions of phosphorylated extracellular signal‐regulated kinase (ERK)1/2, phosphorylated p38 MAPK and NF‐κB p105/p50 in chronic inflammatory skin diseases. An immunohistochemical staining technique was employed to measure the expression of these molecules in 25 cases of lichen planus, 22 cases of psoriasis, 26 cases of chronic eczema, seven cases of prurigo and seven cases of normal skin. We observed that the expression of phosphorylated ERK1/2, phosphorylated p38 MAPK and NF‐κB p105/p50 was significantly more augmented in the lesional epidermis of all the inflammatory skin diseases than those in normal skin (P < 0.05), and the number of positive keratinocytes was significantly more in lichen planus than that in other inflammatory diseases (P < 0.001). Moreover, the positive keratinocytes of these three molecules were more widely distributed in the entire layer of the epidermis in lichen planus than those in other diseases. We concluded that ERK1/2, p38 MAPK and NF‐κB p105/p50 might play important roles in the pathophysiology of chronic inflammatory skin diseases.