BackgroundAcne vulgaris, a common chronic dermatological condition worldwide, is associated with inflammatory response and Cutibacterium acnes. Individuals with acne vulgaris and sensitive skin have limited suitable treatments due to the skin irritation and side effects exhibited by current hydroxy acidic medications.AimsThis study aimed to evaluate the synergistic effects of Guaiacum officinale (GO) and Rhodomyrtus Tomentosa (RT) extracts for treating acne vulgaris on sensitive skin by inhibiting inflammation.MethodsThe phytochemical constituents and antioxidant activity of GO and RT extracts were determined in vitro. The anti‐inflammatory effects were investigated in peptidoglycan (PGN)‐induced HaCaT cells. Further, a 28‐day clinical trial was conducted involving 30 subjects with both sensitive skin and acne to evaluate the efficacy and subjects' satisfaction.ResultsTotal phenolics and flavonoids were detected in GO and RT extracts, the IC50 values for DPPH radical scavenging were 6.15 wt% and 0.76 wt%, respectively. The combination of GO and RT extracts at a 1:1 (v/v) ratio significantly decreased the expression of TLR‐2 and TLR‐4, as well as the secretion of IL‐1α, IL‐8, and TNF‐α in PGN‐induced HaCaT cells, by 2.30–7.93 times compared to GO extract alone (p < 0.05). Moreover, the cream containing 5 wt% the combination significantly improved facial acne and redness (p < 0.05). The number of comedones decreased by 50.00% and papules by 30.65% after 28 days of application. No adverse events were reported and 96.67% of the subjects were satisfied with the treatment.ConclusionThe efficacy of the GO and RT extracts in synergistically suppressing inflammation, improving acne vulgaris, and reducing redness. The study offers an effective and non‐irritant treatment for acne vulgaris in individuals with sensitive skin.