Immunotherapies targeting interleukin (IL)‐17 greatly improve plaque psoriasis. Most previous studies on IL‐17 focused on the T‐helper (Th)17 immune response, but investigation of the effects of IL‐17A on psoriatic epidermal structure are limited. Using an in vitro 3‐D human epidermis model, we investigated the effects of IL‐17A and IL‐17C on morphological changes and gene expression. IL‐17A directly suppressed the formation of the granular layer, whereas IL‐17C did not. IL‐17A significantly downregulated the gene expression of profilaggrin (FLG), which is a major component of keratohyalin granules in the granular layer. Global gene expression analysis of this 3‐D epidermis model showed that both IL‐17A and IL‐17C upregulated S100A7A and type 1 interferon‐related genes including MX1, IFI44L, XAF1 and IFIT1. However, only IL‐17A directly downregulated keratinocyte differentiation‐related and cornified envelope‐related genes including FLG, LOR, C1ORF68, LCE1E, LCE1B, KRT10, CST6 and RPTN. In conclusion, IL‐17A, a systemic inflammatory cytokine, affected keratinization in our 3‐D epidermis model. In contrast, IL‐17C, a locally produced cytokine, did not have strong effects on keratinization. Targeting IL‐17A does not only reduce inflammation but it may also directly affect epidermal differentiation in psoriasis.