Context: Oxidative stress is an important factor modulating skin alterations. Melochia arenosa Benth. (Malvaceae) is a Brazilian plant with antimicrobial activity and antioxidant potential. Objective: The objective of this study is to develop a topical formulation containing antioxidant phenolic-rich extract of M. arenosa and to evaluate its skin permeation profile. Materials and methods: Response surface methodology was used to maximize the total phenolic (TP) content of the extract and its antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2 0 -azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and respiratory burst methods. An emulsion containing 1% optimized extract (OE) was developed and employed photoacoustic spectroscopy (PAS) for the determination of its skin permeation profile. The morphology of the skin was studied in histological sections stained with hematoxylin-eosin. Results and discussion: The optimum conditions predicted for the major extractive efficiency of the phenolics with 100% ethanol led extraction time 101 h and plant:solvent proportion 1:13.5 (w/v). OE presented TP ¼ 724.6 ± 8.2 mg GAE/g extract and scavenging capacity of DPPH (IC 50 value ¼ 11.43 ± 0.14 mg/mL) and ABTS radicals (IC 50 value ¼ 35.42 ± 0.48 mg/mL). The production of ROS by neutrophils after stimulation with phorbol miristate acetate was lower when the OE was present in the reaction medium, endorsing its high antioxidant capacity. The data obtained by PAS indicated that the OE present in the emulsion has permeated and was distributed in the whole skin. No histopathological alterations were observed in the histological analysis. Conclusion: The formulation developed is a promising tool for skin care and could prevent the damage caused by oxidative stress.