This study investigates polysaccharides extracted from Azadirachta indica A. Juss. (neem) leaves (NLP) as potential natural agents for anti-hyperpigmentation and antioxidant skincare applications. We aimed to optimize microwave-assisted extraction (MAE)conditions to enhance multiple biological activities in a single process and to characterizethephysicochemical attributes underlying NLP’s efficacy and safety for topical use. NLPwasextracted using citric acid under MAE. Initial single-factor experiments establishedtheworking ranges for extraction time, buffer-to-raw material (B:R) ratio, and microwave power. A Box–Behnken design was then applied to simultaneously optimize five key responses: extraction yield, monophenolase inhibition, diphenolase inhibition, DPPH radical scavengingactivity, and FRAP reducing capacity. Comprehensive physicochemical evaluation includedUV–Vis spectrophotometry, FTIR analysis, high-performance gel permeationchromatography (HPGPC), pH measurement, determination of chemical and monosaccharidecomposition, molecular weight, degree of esterification, viscosity, and cytotoxicity onHaCaTkeratinocytes. The optimized extraction conditions were an extraction time of 1.43min, aB:R ratio of 22.30 mL/g, and microwave power of 331.84 W, produced NLP with a 7.62%yield. The NLP exhibited strong biological activities, including 86.16%monophenolaseinhibition, 68.18% diphenolase inhibition, 45.55% DPPH radical scavenging activity, andaFRAP value of 0.47 mM. Slight acidity (pH 4.35) was attributed to the presence of uronicacids. Structural analyses revealed a low molecular weight (28.15 kDa), lowdegreeofesterification (13.24%), and low viscosity (25.10 mPa·s), characteristics favorable for topical formulation. Cytotoxicity testing showed high biocompatibility, with HaCaT cell viabilityexceeding 79% at all tested concentrations. Overall, citric-acid-assisted MAEoffers anefficient, green approach for producing neem leaf polysaccharides with potent tyrosinaseinhibition, antioxidant activity, and excellent skin-cell compatibility. These findings highlight NLP as a promising multifunctional bioactive ingredient for future dermatological andcosmeceutical formulations targeting hyperpigmentation and oxidative stress.

Suhaila Sujani is a medical doctor who graduated from the University of Malaya, Malaysia, with a special interest in aesthetic medicine and holding a Professional DiplomainDermatology from the Royal College of Physicians, Ireland. She is a registered and licensedaesthetic doctor in Malaysia with a Letter of Credential and Privilege fromthe MinistryofHealth Malaysia and is actively doing research and development for skincare andhealthsupplement products in collaboration with universities in Malaysia as well as clinical trialsfor her cosmetic and skincare products. She is the director of Zeyls Cosmeceutical Companyand the head of research and innovation development for Zeyls Wellness productsinMalaysia. She has published few publications and accepted in reputed journals.