INTRODUCTION: Histological grading of cutaneous squamous cell carcinoma (cSCC) is crucial for prognosis and treatment decisions, but manual grading is subjective and time-consuming. AIM: This study aimed to develop and validate a deep learning (DL)-based model for automated cSCC grading, potentially improving diagnostic accuracy (ACC) and efficiency. MATERIALS AND METHODS: Three deep neural networks (DNNs) with different architectures (AlexNet, GoogLeNet, ResNet-18) were trained using transfer learning on a dataset of 300 histopathological images of cSCC. The models were evaluated on their ACC, sensitivity (SN), specificity (SP), and area under the curve (AUC). Clinical validation was performed on 60 images, comparing the DNNs' predictions with those of a panel of pathologists. RESULTS: The models achieved high performance metrics (ACC>85%, SN>85%, SP>92%, AUC>97%) demonstrating their potential for objective and efficient cSCC grading. The high agreement between the DNNs and pathologists, as well as among different network architectures, further supports the reliability and ACC of the DL models. The top-performing models are publicly available, facilitating further research and potential clinical implementation. CONCLUSIONS: This study highlights the promising role of DL in enhancing cSCC diagnosis, ultimately improving patient care.