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This study aimed to assess natural oils for their antioxidant and anti-hyaluronidase properties and select the most effective candidate for development into nanoemulsions (NE) for clinical evaluations. The oils were assessed using 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+) and ferric thiocyanate assays for antioxidant properties and an enzyme-substrate reaction assay for anti-hyaluronidase activity. The most potent oil was formulated into conventional emulsions (CE) and NE, which were characterized and evaluated for their stability, both in accelerated and long-term conditions. The irritation potential was assessed using both the hen's eggs chorioallantoic membrane test and a clinical trial. Skin hydration enhancement and skin wrinkle reduction efficacy were clinically assessed. Macadamia integrifolia oil exhibited significant potency as an ABTS•+ radical scavenger, lipid peroxidation inhibitor, and hyaluronidase inhibitor (p < 0.05). Both the CE and NE, comprising 15% w/w oil, 5% w/w Tween® 80 and Span® 80, and 80% w/w DI water, were found to be optimal. NE with an internal droplet size of 112.4 ± 0.8 nm, polydispersity index of 0.17 ± 0.01, and zeta potential of −31.5 ± 1.0 mV, had good stability and induced no irritation. Both CE and NE enhanced skin hydration and reduced skin wrinkles in human volunteers, while NE was outstanding in skin hydration enhancement. [ABSTRACT FROM AUTHOR]