Epidemiological evidence reveals that a BRAF inhibitor (BRAFi) drug vemurafenib (PLX4032) for treating late-stage melanoma could cause cutaneous squamous cell carcinoma in cancer patients with the most prevalent HRAS^Q61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) resemble the lesions in BRAF inhibitor-treated patients. We investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM) against PDV cells, mouse keratinocytes bearing HRAS^Q61L mutation, and its effect on inhibiting papilloma formation in a two stage skin carcinogenesis mouse model, with or without PLX4032 co-treatment. The results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. KWM-EO treatment significantly decreased the formation of cutaneous papilloma in DMBA/TPA mice or in BRAFi PLX4032 further irritated DMBA/TPA mice (DMBA/TPA/BRAFi). Immunohistochemistry analyses showed that infiltration of inflammatory cell infiltration (neutrophils/elastase, macrophages/F4/80), and overexpression of keratin14 and COX-2 in DMBA/TPA and DMBA/TPA/BRAFi mice skins were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and that is worth further exploration for possible application in melanoma patients.