Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. Today, cSCC is diagnosed by visual inspection followed by invasive skin biopsy. There is a need to develop non-invasive diagnostic tools to achieve early and accurate detection. Photoacoustic imaging (PAI) possesses high ultrasonic resolution and strong optical contrast at new depths (<1-5 cm). Together with exogenous contrast agents, PAI has found promising use in various tumors in living subjects. The expression of integrin αvβ6 is significantly up-regulated in cSCC. We fabricated an anti-integrin αvβ6 antibody and labeled it with indocyanine green (ICG) to form an ICG-αvβ6 antibody. The results showed that the ICG-αvβ6 antibody probe could be used to detect cSCC with high specificity (3-fold over the control by PAI) and deep penetration (approximately 1 cm) by PAI. This suggests that the ICG-αvβ6 antibody is a promising probe targeting the integrin αvβ6 for detection of cSCC tumors by PAI and fluorescence imaging. It may find clinical application in the early diagnosis of cSCC as well as in intraoperative navigation.