Hyperpigmentation is a common concern of patients in aesthetic practice. There are various treatment options, but topical depigmenting agents such as hydroquinone (HQ) are usually a first-line option. Given HQ's side effects and potential controversy over its long-term use from prior animal studies, there is a consumer demand for non-HQ topical formulations that provide similar efficacy, but with a reduced adverse reaction profile to HQ. There is increasing evidence to support the use of selective growth factors, tranexamic acid, niacinamide, arbutin, and Vitamin C in improving hyperpigmentation. This study sought to determine whether a non-HQ topical formulation, composed of the aforementioned ingredients, could provide similar or improved efficacy to topical HQ, but with a reduced adverse reaction profile. This single-center, prospective, randomized, controlled split face study investigated the safety and efficacy of a proprietary product SKNB19 compared with hydroquinone 4% (HQ4%) in treating hyperpigmentation. Eighteen adult subjects with facial pigmentation were randomly assigned to have one side of their face treated with SKNB19 twice a day (morning and night application) and the other treated with HQ4% applied nightly. Patients used a 5-point scale to self-assess their overall appearance, and a 4-point scale to assess redness, irritation, and tolerability to the skin-brightening creams. A Wilcoxon signed-rank test was used to test whether there was a statistical difference between the two treatments. Three-dimensional imaging was performed before treatment was administered and again 1 month following treatment initiation using a Canfield Vectra 3D imaging system. Five independent reviewers comprising two dermatologists, two facial plastic surgeons, and one oculoplastic surgeon graded and performed a qualitative comparative assessment of each side of the face using the before and after images. A Wilcoxon signed-rank test was used to test whether there was a statistical difference in overall appearance between SKNB19- and HQ4%-treated sides. SKNB19-treated hyperpigmentation had a statistically significant improvement in the overall appearance of hyperpigmentation and was shown to be 28.5% better than HQ4%-treated skin in the patient self-assessment and 27% better than HQ4%-treated skin in the independent reviewer assessment. On pair-wise comparison, the independent reviewer assessment also showed that 88.2% of the SKNB19-treated sides appeared equal or better than the HQ4%-treated sides. One patient dropped out of the study because of severe intolerance to HQ4%. No patients experienced intolerance to SKNB19, and all were able to continue its use without adverse effects. SKNB19-treated hyperpigmentation also had a statistically significant reduction in irritation when compared with HQ4%-treated hyperpigmentation. Patients reported a reduction in redness when using SKNB19 as opposed to HQ4%, but these figures did not reach statistical significance. This study supports that SKNB19, a recently developed non-HQ proprietary product, is safe and effective in improving hyperpigmentation. SKNB19 significantly improved the appearance of hyperpigmentation when compared with HQ4% in both patient self-assessment and independent reviewer assessment. SKNB19 exhibited a lower adverse reaction profile and was significantly better tolerated than HQ4%. SKNB19 should be considered as a safe and effective non-HQ alternative for the management of hyperpigmentation.