Cutaneous field cancerization (CFC) is associated with a high-risk of developing cutaneous squamous cell carcinoma (cSCC). It manifests as actinic keratoses (AK) as one of the few macroscopic alterations in CFC patients. A prospective, single-arm, case-series was performed to evaluate the utility of a novel sunscreen containing DNA-photolyase for treatment of CFC in nine subjects (mean age 70.6 years, male: female ratio 5:4). The cream was applied topically twice daily on CFC/AK areas and patients were followed up for three months, with no other treatments. The primary outcome was the overall response rate (ORR), categorized as complete response (CR, complete resolution of AKs), partial response (PR, reduction in the number of AKs), and no-response (NR, similar/ increase in number of AKs). A 100% PR was observed. All subjects displayed at minimum, a 50% reduction in their lesion number and most patients experienced almost CR. Evaluation of AK numbers revealed an absolute count reduction of 76.6% in the number of lesions, with the mean number of lesions reduced from 13.4 to 3.1 (p < 0.0001). No adverse events were reported. Patients with CFC may benefit from novel topical applications containing DNA-photolyase, at minimum, as complementary therapy for the management of CFC disease. We propose a new concept called “active photoprotection” because of its dual mechanism involving therapy and protection.