Actinic Cheilitis (AC) is a pathological condition of the labial mucosa considered potentially malignant. The aim of this study was to investigate the effect of treatment of AC with daily use of a vitamin-based barrier cream. For this clinical study, 36 participants with lower-lip AC were recruited from three oral medicine services. At baseline, participants were evaluated by clinical examination and clinical severity of AC was classified as grade I to IV. All participants were dispensed a tube of a barrier cream containing vitamins A, D, E and ZnO to apply once nightly for 90 consecutive days. Monthly follow-up was performed to reclassify AC clinial severity. The primary outcome of interest was clinical remission of AC at 90-day follow-up compared to baseline. Progressive remission of AC lesions was observed as early as the first month and throughout the assessment period (p = 0.000). The 3-month period was insufficient for remission of lesions, especially among male participants (p = 0.002) and with a longer sun exposure in years (p = 0.007). Daily use of the vitamin-based barrier cream had a promissing positive impact on the severity of actinic cheilitis. However, a 90-day course of treatment was not sufficient to achieve lesions remission. The findings of this study suggest a promising new avenue for the treatment of lower-lip AC.