Acne vulgaris is a chronic inflammatory skin disease in which a defect in the immune barrier function is a major extent of the pathological etiology. The aim of this randomized controlled trial was to assess the restorative benefits of supramolecular salicylic acid (SSA) with intense pulsed light (IPL) photon rejuvenation and its effects on the immune barrier function of the skin in acne patients. Moderate-to-severe acne was assigned to each patient, with three groups being treated for 12 weeks with either: The primary outcome was transepidermal water loss (TEWL) (continuous variable); secondary outcomes were stratum corneum hydration, sebum secretion, skin pH, pro- and anti-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10, TGF-β), Treg/Th17 cell ratio, microbiome Shannon diversity index, Global Acne Grading System (GAGS) score, lesion counts, and the Dermatology Life Quality Index (DLQI). The SSA+IPL group showed significant improvements compared to both monotherapy groups in all outcomes (all corrected p < 0.001). TEWL decreased by 47.0% (Cohen's d = 2.14; 95% CI: 1.67–2.61), stratum corneum hydration increased by 67.0%, and sebum secretion declined by 45.7%. Fifty-six to 58% reduction in pro-inflammatory cytokines was achieved, whereas IL-10 and TGF-β levels increased by 167.8% and 130.8% respectively. The ratio Treg/Th17 was raised by 331.3% and Shannon diversity index was raised by 52.1%. This multiple regression revealed that the Treg/Th17 ratio reestablishment, reduction of sebum and upregulation of IL-10 are independent factors of clinical efficacy (adjusted R² = 0.763). The combination of SSA and IPL therapy can have a systemic effect on the regeneration of skin immune barrier function by overlapping mechanisms and deserves further testing in larger trials.