Actinic keratosis (AK), Bowen’s disease (BD) and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions (KSL). Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalised, precise management of skin neoplasia. In this paper, we used the SWATH proteomics workflow to analyse formalin-fixed paraffin embedded (FFPE) samples of normal skin and KSL including well differentiated (WD), moderately differentiated (MD) and poorly differentiated (PD) cSCC. We identified and quantified 3574 proteins across 93 samples studied. Differential abundance analysis identified 19, five and six protein markers exclusive to AK, BD and cSCC lesions, respectively. Among cSCC lesions of various levels of tumour differentiation, 118, 230 and 17 proteins showed potential as biomarkers of WD-, MD- and PD-cSCC lesions, respectively. Bioinformatics analysis revealed that AK and cSCC lesions were associated with decreased apoptosis and BD lesions with over-representation of DNA damage repair pathway. Differential expression of FGFR2 alternative splicing, Rho GTPase signalling, and RNA metabolism proteins were associated with the level of cSCC tumour differentiation. Proteome profiles also separated all KSL subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate KSL subtypes and facilitate new diagnostic and therapeutic strategies.