Objective To explore the impact of ten-eleven translocation 2 (TET2) mutations on imiquimod (IMQ)-induced psoriatic skin inflammation using a TET2-knockout (TET2^-/-) mouse model. Methods Mice were divided randomly into a wild-type (WT) vaseline group, WT imiquimod group, TET2^-/- vaseline group, and TET2^-/- imiquimod group. IMQ was used to establish a psoriasis-like dermatitis model, and the degree of skin lesions and pathological changes in mice in the WT imiquimod and TET2^-/- imiquimod groups were observed and compared daily during the modeling period. The mice were sacrificed when the phenotype had reached the peak and the spleen index was recorded in each group. Gene expression levels of the inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A, and IL-23 in mouse back lesions were detected by quantitative reverse transcription polymerase chain reaction. Skin histopathology was compared in hematoxylin/eosin-stained sections. IL-17, interferon (INF)-γ, and TNF-α protein expression levels in the back skin of mice in the four groups were detected by immunohistochemistry. The ultrastructure of the dermis and epidermis was observed using transmission electron microscopy. Results TET2 expression was down-regulated in skin lesions in WT imiquimod group. Dermatitis lesions were more severe and progressed faster in TET2^-/- imiquimod group compared with WT imiquimod group, and the psoriasis area and severity index score and spleen index were both higher. mRNA expression levels of TNF-α, IL6, IL-17A, and IL-23 in skin lesions were higher and epidermal thickening and inflammatory cell infiltration were increased, and protein expression levels of IL-17, INF-γ, and TNF-α were significantly higher in skin lesions in TET2^-/- imiquimod group compared with WT imiquimod group. In addition, cell junctions were absent in skin lesions in TET2^-/- imiquimod group and mitochondrial ridges were broken and dissolved, mitochondrial vacuoles were present, and the texture of the mitochondrial membrane was darker. Conclusions Loss of TET2 promotes the inflammatory response and exacerbates IMQ-induced psoriasis-like dermatitis injury in mice.