Purpose. Sensitive scalp (SScalp) is characterized by abnormal and nociceptive sensations, such as stinging and itching, that lead to scalp discomfort. This study assessed the benefit of a once-daily serum containing Adenosine, Magnesium Sulfate (MgSO4), Vitamin C Glucoside (CG), and pre- and probiotic fractions in subjects with SScalp. Methods. An open-label, single center study in adult subjects with a Global Scalp Discomfort (GSD) score of ≥8 (0–27), defined as the sum of individual symptom scores (0–9) for itching, stinging, and warming sensations. The frequency of scratching was self-declared. Evaluations were performed immediately after the 1st application (D0Timm) and at D21, during which the cosmetic acceptability was additionally assessed. Transepidermal water loss and skin hydration were assessed at baseline, D21, and D28. Squalene (SQ) and SQOOH were analyzed at D0T0, D21T0, and D28. Tolerance was assessed throughout the study. Results. 42 subjects (30 women and 12 men) participated in this study. The mean age was 44.0 ± 13.0 years. At baseline, the mean GSD was 13.9 ± 3.28. The GSD and symptoms significantly
p
<
0.0001
improved at D0Timm and lasted until the end of the study (D28), with insignificant worsening. There was a significant reduction of SQOOH at D21 and D28. Subject satisfaction was high, associated with a good tolerance. A similar and significant
p
<
0.0001
improvement was observed for subjects with more severe symptoms and a GSD score ≥14 at baseline. Conclusion. The topical serum significantly reduces SScalp, global discomfort, and oxidative stress and is beneficial in the management of sensitive scalp. This TRIAL is registered with NCT05630027.