Deltamethrin, a pyrethroid insecticide, used extensively for pest control has been reported to cause adverse health effects including carcinogenic/toxic effects in animals but the underlying mechanism remains elusive. In the present study, we investigated the effect of deltamethrin after short exposure on early protein expression changes involved in neoplastic transformation in mouse skin, validated the results in human keratinocyte HaCaT cells and thereby explore the possible underlying mechanism. Deltamethrin (4 mg/kg b.wt) and benzo[a]pyrene (B[a]P, 0.05 mg/kg b.wt) were topically applied on Swiss albino mice, respectively. The comparative protein expression profiles with vehicle control were generated by 2-dimensional gel electrophoresis (2-DE) and mass spectrometry. 2-DE maps of deltamethrin and B[a]P treated mouse skin showed 20 and 24 significant (2 fold change, p < 0.05) differentially expressed protein spots, against vehicle controls. However, comparison between them showed relatively similar expression level of 20 spots. Among them, 5 proteins (carbonic anhydrase III, peroxiredoxin-2, calcyclin, superoxide dismutase [Cu-Zn], ubiquitin) are of particular significance as these are involved in cancer-related key processes. Deregulation of these was confirmed at protein and mRNA levels by immunoblotting and RT-PCR in mouse skin and HaCaT cells. Therefore, we conclude that these preliminarily identified proteins might be responsible for the neoplastic transformation of mouse skin epidermal cells and HaCaT cells by deltamethrin. This study proposes complementary mechanism where inhibition of proteasome activator protein (PA200) is responsible for accumulation of ubiquitinated-calcyclin, regulates deltamethrin-induced neoplastic changes in mouse skin and HaCaT cells.