In previous studies, Perilla frutescens pomace was shown to contain bioactive phenolic compounds and good anti-oxidative activity. However, reports about collagenase activity and melanogenesis inhibitory effects of P. frutescens pomace are limited. This study aimed to evaluate the bioactivity of P. frutescens pomace extract and incorporate the extract into a cosmetic formulation for evaluating its effects on collagenase and melanogenesis inhibition on human skin. The P. frutescens seeds after an oil pressing process were extracted with ethanol (70% v/v) in order to examine the remaining phytochemical compounds, the bioactivity in pomace perilla, and its efficacy as a skincare product. In this study, total phenolic and total flavonoid contents of P. frutescens seed extract (PFSE) were determined using spectrophotometry. The free radical scavenging activity was determined with 2, 2′-diphenyl-1-picrylhydrazyl (DPPH) radicals and 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) ABTS radicals. Additionally, the effects on collagenase activity, melanin content, and alpha-Melanocyte stimulating hormone (α-MSH) on the viability of cultured B16F10 melanoma cells were investigated. Skin irritation and efficacy of PFSE cream for skin elasticity and skin color were also clinically evaluated. The total phenolic content with gallic acid equivalents (GAE) value and total flavonoids content with catechin equivalents (CE) value were, respectively, 92.79 ± 1.19 and 56.02 ± 2.83 mg/g. Furthermore, PFSE significantly inhibited the collagenase activity (p < 0.001) at the concentration of 400 µg/mL (82 ± 3.23%). These results clearly demonstrated the anti-melanogenic effects on B16F10 cells without causing any cytotoxicity or death. Although there was a slight improvement in skin elasticity in the 4th week compared to the previous week, the 4th week melanin content of the skin significantly decreased from the beginning (p < 0.05) without any irritations. In conclusion, PFSE could be cosmetically considered as a key ingredient that effectively lessens the effects of skin aging and skin hyperpigmentation disorders.