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Background: Actinic keratosis is a common precancerous skin lesion that can progress into invasive squamous cell carcinomas. Many topical treatments for actinic keratoses often have poor tolerability and prolonged duration. Tirbanibulin is a novel synthetic drug with potent antitumor and antiproliferative activities. Methods: We conducted a single-center, prospective and observational study using tirbanibulin ointment on a 25 cm2 area for 5 consecutive days on 30 participants with AKs on the face or scalp. They were followed for at least 57 days to assess the safety profile and efficacy of the drug as well as treatment satisfaction. We evaluated six signs of local skin reaction (LSR): erythema, scaling, crusting, swelling, blisters/pustules, and erosions/ulcerations, grading the severity as mild, moderate, or severe. The effectiveness was evaluated both clinically and dermoscopically. The treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Results: On day 57, 70% of the patients showed a complete clinical and dermoscopic response. The highest scores obtained from the TSQM 1.4 were more evident in the convenience and side effects domains. Most LSRs, including erythema (83.3%), scaling (30%), and swelling (3.3%), occurred on day 8 but resolved spontaneously. Conclusion: Tirbanibulin is a viable therapeutic option with a short regimen treatment and good tolerability, which favors therapy adherence.