Epidermal squamous cell carcinoma (SCC) and mesothelioma are two distinct but highly aggressive forms of cancer. SCC is a common and highly invasive cancer that arises from the epidermis. The major cause of epidermal SCC is repeated exposure to ultraviolet light and other DNA damaging agents such as oxidative stress which causes mutations eventually leading to increased expression of pro-tumor genes and reduced expression of tumor suppressors. Mesothelioma is highly invasive and lethal cancer that arises from the mesothelial lining and is linked to exposure to asbestos and other toxic agents. Actin-like protein 6A (ACTL6A, BAF53A) is a member of SWI/SNF chromatin remodeling complex that has been implicated in many cancers as a driver of cancer survival and tumor formation. We show that ACTL6A functions to maintain an aggressive cancer phenotype in both SCC and mesothelioma. We further show that ACTL6A reduces expression of the p21Cip1 cyclin-dependent kinase inhibitor and tumor suppressor protein. Biochemical studies reveal that loss of ACTL6A leads to increased p21Cip1 promoter activity, and mRNA and protein expression suggesting transcriptional regulation of p21Cip1 gene. Moreover, chromatin immunoprecipitation studies show that ACTL6A interacts at the p21Cip1 promoter proximal Sp1 site and distal p53-responsive enhancer sites to suppress transcription. We further report that the increase in p21Cip1 upon ACTL6A knockdown is required to suppress the SCC and mesothelioma cancer phenotypes. This suggests that p21Cip1 is the key mediator of ACTL6A function in SCC and mesothelioma. p53 is a key tumor suppressor that interacts with the p21Cip1 promoter to increase expression; however, we show that it may not play a regulatory role in these cancers. These findings suggest that ACTL6A suppresses p21Cip1 transcription to reduce p21Cip1 function as a mechanism to maintain an aggressive cancer phenotype in SCC and mesothelioma.