Cutaneous squamous cell carcinoma (CSCC) is the most common keratinocyte-derived skin cancer in the Caucasian population. Exposure to UV radiations (UVRs) represents the main risk carcinogenesis, causing a considerable accumulation of DNA damage in epidermal keratinocytes with an uncontrolled hyperproliferation and tumor development. The limited and rarely durable response of CSCC to the current therapeutic options has led researchers to look for new therapeutic strategies. Recently, the multi-omics approaches have contributed to the identification and prediction of the key role of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), circularRNAs (circRNAs) and long non-coding RNAs (lncRNAs) in the regulation of several cellular processes in different tumor types, including CSCC. ncRNAs can modulate transcriptional and post-transcriptional events by interacting either with each other or with DNA and proteins, such as transcription factors and RNA-binding proteins. In this review, the implication of ncRNAs in tumorigenesis and their potential role as diagnostic biomarkers and therapeutic targets in human CSCC are reported.