Background: While cannabidiol (CBD) and 4’,7-isoflavandiol (Equol) have been examined individually in various skin studies, the present investigation tested whether topically applied CBD with Equol may yield enhanced effects on human skin biomarkers. Methods: After 24 hours exposure human skin gene expression was measured by quantitative polymerase chain reaction-messenger ribonucleic acid (qPCR-mRNA) analysis across 9 functional skin categories covering 97 biomarkers. Results: In general, among the biomarkers analyzed the CBD with Equol treatment displayed greater efficacy compared to CBD only or the Equol treatment alone (e.g., 4 out 5 for anti-acne, 15 out of 17 for anti-aging [e.g., collagen, elastin, calcium binding protein A7, tissue inhibitor of matrix metalloproteinase 1 (TIMP 1), etc.], 19 out of 21 for anti-inflammatory (pain), 10 out of 11 for antioxidants to protect against oxidative stress, 6 out of 6 for circadian rhythm regulation for cell repair/restoration, 10 out of 15 for anti-pigmentation properties, 4 out of 5 for skin hydration, 6 out of 6 for tissue integrity, and 11 out of 12 for wound healing properties). Conclusions: CBD with Equol displayed synergistic effects that may be an effective topical treatment for dermatology and cosmetic applications to improve human skin health and reduce photo-aging.