Ubiquitin like with PHD and ring finger domains 1 (UHRF1) contributes to the progression of many cancers. Here, we firstly observed UHRF1 was elevated in cutaneous squamous cell carcinoma (cSCC) and related to the differentiation stages. Knockdown of UHRF1 in A431 and Scl-1 attenuated cell proliferation, migration, and invasion, leading to G2/M cell cycle arrest and apoptosis. Through a mouse xenograft model, we found UHRF1 deficiency ameliorated tumor growth. These results may be associated with destruction of multiple signal pathways. In summary, our results suggest UHRF1 is involved in the pathogenesis of cSCC and may be a therapeutic target.